Short duration depot formulations

ABSTRACT

Methods and compositions for systemically or locally administering by implantation a beneficial agent to a subject are described, and include, for example, depot gel compositions that can be injected into a desired location and which can provide controlled release of a beneficial agent over a short duration of time. The compositions include a low molecular weight biocompatible polymer, a biocompatible solvent having low water miscibility that forms a viscous gel with the polymer and limits water uptake by the implant, and a beneficial agent.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.15/267,070, filed Sep. 15, 2016, now U.S. Pat. No. 10,201,496, whichapplication is a continuation of U.S. application Ser. No. 11/278,472,filed Apr. 3, 2006, which application is a divisional of U.S.application Ser. No. 10/606,969, filed Jun. 25, 2003, entitled “SHORTDURATION DEPOT FORMULATIONS” which claims the benefit of U.S.Provisional Application No. 60/391,867, filed on Jun. 25, 2002. Thecontents of the above referenced applications are hereby incorporated intheir entirety by reference.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a depot gel composition that can beinjected into a desired location and which can provide controlledrelease of a beneficial agent over a short duration of time. The presentinvention also relates to a method of preparing and administering thecomposition.

Description of the Related Art

Biodegradable polymers have been used for many years in medicalapplications. Illustrative devices composed of the biodegradablepolymers include sutures, surgical clips, staples, implants, and drugdelivery systems. The majority of these biodegradable polymers have beenbased upon glycolide, lactide, caprolactone, and copolymers thereof.

The biodegradable polymers can be thermoplastic materials, meaning thatthey can be heated and formed into various shapes such as fibers, clips,staples, pins, films, etc. Alternatively, they can be thermosettingmaterials formed by crosslinking reactions, which lead tohigh-molecular-weight materials that do not melt or form flowableliquids at high temperatures. Although thermoplastic and thermosettingbiodegradable polymers have many useful biomedical applications, thereare several important limitations to their use in the bodies of variousanimals including humans, animals, birds, fish, and reptiles.

Solid implant drug delivery systems containing a drug incorporated inthermoplastic or thermosetting biodegradable polymers have been widelyused successfully. Such implants have to be inserted into the bodythrough an incision which is sometimes larger than desired by themedical profession and occasionally lead to a reluctance of the patientsto accept such an implant or drug delivery system. The following U.S.Pat. Nos. 5,456,679; 5,336,057; 5,308,348; 5,279,608; 5,234,693;5,234,692; 5,209,746; 5,151,093; 5,137,727; 5,112,614; 5,085,866;5,059,423; 5,057,318; 4,865,845; 4,008,719; 3,987,790 and 3,797,492 arebelieved to be representative of such drug delivery systems and areincorporated herein by reference. These patents disclose reservoirdevices, osmotic delivery devices and pulsatile delivery devices fordelivering beneficial agents.

Injecting drug delivery systems as small particles, microspheres, ormicrocapsules avoids the incision needed to implant drug deliverysystems. However, these materials do not always satisfy the demand for abiodegradable implant. These materials are particulate in nature, do notform a continuous film or solid implant with the structural integrityneeded for certain prostheses, the particles tend to aggregate and thustheir behavior is hard to predict. When inserted into certain bodycavities such as a mouth, a periodontal pocket, the eye, or the vaginawhere there is considerable fluid flow, these small particles,microspheres, or microcapsules are poorly retained because of theirsmall size and discontinuous nature. Further, if there arecomplications, removal of microcapsule or small-particle systems fromthe body without extensive surgical intervention is considerably moredifficult than with solid implants. Additionally, manufacture, storageand injectability of microspheres or microcapsules prepared from thesepolymers and containing drugs for release into the body presentproblems.

The art has developed various drug delivery systems in response to theaforementioned challenges. The following U.S. Pat. Nos. 5,990,194;5,780,044; 5,733,950; 5,620,700; 5,599,552; 5,556,905 5,278,201;5,242,910 and 4,938,763; and PCT publication WO 98/27962 are believed tobe representative and are incorporated herein by reference. Thesepatents disclose polymer compositions for injectable implants usingsolvents and/or plasticizers.

Previously described polymer compositions for injectable implants haveused solvent/plasticizers that are very or relatively soluble in aqueousbody fluids to promote rapid solidification of the polymer at theimplant site and promote diffusion of drug from the implant. Rapidmigration of water into such polymeric implants utilizing water solublepolymer solvents when the implants are placed in the body and exposed toaqueous body fluids presents a serious problem. The rapid water uptakeoften results in implants having pore structures that arenon-homogeneous in size and shape. Typically, the surface pores take ona finger-like pore structure extending for as much as one-third of amillimeter or more from the implant surface into the implant, and suchfinger-like pores are open at the surface of the implant to theenvironment of use. The internal pores tend to be smaller and lessaccessible to the fluids present in the environment of use. The rapidwater uptake characteristic often results in uncontrolled release ofbeneficial agent that is manifested by an initial, rapid release ofbeneficial agent from the polymer composition, corresponding to a“burst” of beneficial agent being released from the implant. The burstoften results in a substantial portion of the beneficial agent, if notall, being released in a very short time, e.g., hours or 1-2 days. Suchan effect can be unacceptable, particularly in those circumstances wherea controlled delivery is desired, i.e., delivery of beneficial agent ina controlled manner over a period of greater than or equal to 3 days orup to a month, or where there is a narrow therapeutic window and releaseof excess beneficial agent can result in adverse consequences to thesubject being treated, or where it is necessary to mimic thenaturally-occurring daily profile of beneficial agents, such as hormonesand the like, in the body of the subject being treated.

Accordingly, when such devices are implanted, the finger-like poresallow very rapid uptake of aqueous body fluids into the interior of theimplant with consequent immediate and rapid dissolution of significantquantities of beneficial agent and unimpeded diffusion of beneficialagent into the environment of use, producing the burst effect discussedabove.

Furthermore, rapid water uptake can result in premature polymerprecipitation such that a hardened implant or one with a hardened skinis produced. The inner pores and much of the interior of the polymercontaining beneficial agent are shut off from contact with the bodyfluids and a significant reduction in the release of beneficial agentcan result over a not insignificant period of time (“lag time”). Thatlag time is undesirable from the standpoint of presenting a controlled,sustained release of beneficial agent to the subject being treated. Whatone observes, then, is a burst of beneficial agent being released in ashort time period immediately after implantation, a lag time in which noor very little beneficial agent is being released, and subsequentlycontinued delivery of beneficial agent (assuming beneficial agentremains after the burst) until the supply of beneficial agent isexhausted.

Various approaches to control burst and modulate and stabilize thedelivery of the beneficial agent have been described. The following U.S.Pat. Nos. 6,130,200; 5,990,194; 5,780,044; 5,733,950; 5,656,297;5,654,010; 4,985,404 and 4,853,218 and PCT publication WO 98/27962 arebelieved to be representative and are incorporated herein by reference.Notwithstanding some success, those methods have not been entirelysatisfactory for the large number of beneficial agents that would beeffectively delivered by implants.

SUMMARY OF THE INVENTION

The present invention provides a method and an injectable depot gelcomposition for systemic and local delivery of a beneficial agent to asubject over a short duration of time. In particular, the inventionprovides controlled release of the beneficial agent to the subject beingtreated, the release being controlled over a period equal to or lessthan two weeks after administration, preferably a period of about 3 toabout 7 days. Additionally, the invention provides a method of preparingthe injectable depot gel composition.

In one aspect, the invention pertains to an injectable depot compositioncomprising a low molecular weight bioerodible, biocompatible polymer; asolvent having a miscibility in water of less than or equal to 7 wt. %at 25° C., in an amount effective to plasticize the polymer and form agel therewith; and a beneficial agent dissolved or dispersed in the gel.Preferably the solvent has a miscibility in water of less than 7 wt. %,more preferably less than 5 wt %, and more preferably less than 3 wt %.

In another aspect, the invention pertains to an injectable depotcomposition for systemic delivery of a beneficial agent to a subject ina controlled manner over a duration equal to or less than two weekscomprising a low molecular weight bioerodible, biocompatible polymer; asolvent having a miscibility in water of less than or equal to 7 wt. %at 25° C., in an amount effective to plasticize the polymer and form agel therewith; and a beneficial agent dissolved or dispersed in the gel.

In an additional aspect, the invention pertains to an injectable depotcomposition for sustained delivery of a beneficial agent to a subjectcomprising a low molecular weight bioerodible, biocompatible polymer; asolvent having a miscibility in water of less than or equal to 7 wt. %at 25° C., in an amount effective to plasticize the polymer and form agel therewith; and a beneficial agent dissolved or dispersed in the gel;wherein the beneficial agent is delivered systemically in a controlledmanner over a duration equal to or less than two weeks, preferably about24 hours to about 2 weeks, preferably about 10 days or shorter;preferably about 7 days or shorter, more preferably about 3 days toabout 7 days.

In an additional aspect, the invention pertains to an injectable depotcomposition for sustained delivery of a beneficial agent to a subjectcomprising a low molecular weight bioerodible, biocompatible polymer; asolvent having a miscibility in water of less than or equal to 7 wt. %at 25° C., in an amount effective to plasticize the polymer and form agel therewith; and a beneficial agent dissolved or dispersed in the gel;wherein the beneficial agent is delivered locally in a controlled mannerover a duration equal to or less than two weeks, preferably about 24hours to about 2 weeks, preferably about 10 days or shorter; preferablyabout 7 days or shorter, more preferably about 3 days to about 7 days.

In another aspect, the invention pertains to an injectable depotcomposition as described above, further including at least one of thefollowing: a pore former; a solubility modulator for the beneficialagent; and an osmotic agent; and optionally including an emulsifyingand/or a thixotropic agent.

In another aspect, the invention pertains to an injectable depotcomposition as described above, wherein the low molecular weight polymerhas a weight average molecular weight ranging from about 3000 to about10,000; preferably from about 3000 to about 9,000; more preferably fromabout 4000 to about 8,000; and more preferably the low molecular weightpolymer has a molecular weight of about 7000, about 6000, about 5000,about 4000 and about 3000.

In another aspect, the invention pertains to an injectable depotcomposition as described above, wherein the polymer is selected from thegroup consisting of polylactides, polyglycolides, polyanhydrides,polyamines, polyesteramides, polyorthoesters, polydioxanones,polyacetals, polyketals, polycarbonates, polyphosphoesters,polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid),poly(amino acids), polyvinylpyrrolidone, polyethylene glycol,polyhydroxycellulose, chitin, chitosan, hylauronic acid and copolymers,terpolymers and mixtures thereof. In preferred embodiments, the polymeris a lactic acid-based polymer; preferably the polymer is a copolymer oflactic acid and glycolic acid.

In another aspect, the invention pertains to an injectable depotcomposition as described above, wherein the solvent is selected from anaromatic alcohol having the structural formula (I)Ar-(L)_(n)-OH  (I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group,n is zero or 1, and L is a linking moiety; and a solvent selected fromthe group consisting of esters of aromatic acids, aromatic ketones, andmixtures thereof.

In preferred embodiments, the solvent is selected from the aromaticalcohol, lower alkyl and aralkyl esters of aryl acids; aryl, aralkyl andlower alkyl ketones; and lower alkyl esters of citric acid. Preferably,the solvent is selected from benzyl alcohol, benzyl benzoate and ethylbenzoate. In preferred embodiments, the composition is free of solventshaving a miscibility in water that is greater than 7 wt. % at 25° C.

In additional aspects, the invention pertains to methods ofadministering a beneficial agent to a subject in a controlled mannerover a duration equal to or less than two weeks, comprisingadministering an injectable depot composition as described above. Incertain embodiments, the beneficial agent is delivered systemically in acontrolled manner over a duration equal to or less than two weeks. Inadditional embodiments, the beneficial agent is delivered locally in acontrolled manner over a duration equal to or less than two weeks. Inpreferred embodiments, the beneficial agent is delivered over a durationof about 24 hours to about 2 weeks, preferably about 10 days or shorter;preferably about 7 days or shorter, more preferably about 3 days toabout 7 days.

In additional aspects, the invention pertains to a kit foradministration of a beneficial agent to a subject comprising:

(a) a low molecular weight bioerodible, biocompatible polymer;

(b) a solvent having a miscibility in water of less than or equal to 7wt. % at 25° C. that is suitable for dissolving the polymer and forminga viscous gel;

(c) a beneficial agent; and optionally, one or more of the following:

(d) an emulsifying agent;

(e) a pore former;

(f) a solubility modulator for the beneficial agent, optionallyassociated with the beneficial agent; and

(g) an osmotic agent;

wherein at least the beneficial agent, optionally associated with thesolubility modulator, is maintained separated from the solvent until thetime of administration of the beneficial agent to a subject.

In another aspect, the invention pertains to an injectable depotcomposition and a method of administering such composition as describedabove, wherein the beneficial agent is selected from a drug, proteins,enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides,glycoproteins, lipoproteins, polypeptides, steroids, analgesics, localanesthetics, antibiotic agents, chemotherapeutic agents,immunosuppressive agents, anti-inflammatory agents, antiproliferativeagents, antimitotic agents, angiogenic agents, antipsychotic agents,central nervous system (CNS) agents, anticoagulants, fibrinolyticagents, growth factors, antibodies, ocular drugs, and metabolites,analogs, derivatives, fragments, and purified, isolated, recombinant andchemically synthesized versions of these species. In preferredembodiments, the beneficial agent is human growth hormone,methionine-human growth hormone; des-phenylalanine human growth hormone,alpha-, beta- or gamma-interferon, erythropoietin, glugacon, calcitonin,heparin, interleukin-1, interleukin-2, Factor VIII, Factor IX,luteinizing hormone, relaxin, follicle-stimulating hormone, atrialnatriuretic factor, filgrastim epidermal growth factors (EGFs),platelet-derived growth factor (PDGFs), insulin-like growth factors(IGFs), fibroblast-growth factors (FGFs), transforming-growth factors(TGFs), interleukins (ILs), colony-stimulating factors (CSFs, MCFs,GCSFs, GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF,EGFs), erythropoietin (EPOs), angiopoietins (ANGs), placenta-derivedgrowth factors (PlGFs), and hypoxia induced transcriptional regulators(HIFs). Preferably, the beneficial agent is present in an amount of from0.1 to 50% by weight of the combined amounts of the polymer, the solventand the beneficial agent. In preferred embodiments, the beneficial agentis in the form of particles dispersed or dissolved in the viscous gel,wherein the beneficial agent is in the form of particles having anaverage particle size of from 0.1 to 250 microns. In certain preferredembodiments, the beneficial agent is in the form of particles whereinthe particle further comprises a component selected from the groupconsisting of a stabilizing agent, bulking agent, chelating agent and abuffering agent.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of the presentinvention will be more readily understood upon reading the followingdetailed description in conjunction with the drawings as describedhereinafter.

FIG. 1 is a graph illustrating the in vivo release profile ofbupivacaine hydrochloride obtained from depot formulations of thepresent invention (formulations 1-2).

FIG. 2 is a graph illustrating the in vivo release profile ofbupivacaine base obtained from depot formulations of the presentinvention (formulations 3-4).

FIG. 3 is a graph illustrating the in vivo release profile ofbupivacaine base obtained from a depot formulation of the presentinvention (formulation 4).

FIG. 4 is a graph illustrating the in vivo release profile of humangrowth hormone (hGH) obtained from depot formulations of the presentinvention (formulations 5-6).

FIG. 5 is a graph illustrating the in vivo release profile of hGHobtained from a depot formulation of the present invention (formulation6).

FIG. 6 is a graph illustrating the in vivo release profile of hGHobtained from depot formulations of the present invention (formulations6-7)

FIG. 7 is a graph illustrating the in vivo release profile ofbupivacaine obtained from depot formulations of the present invention(formulations 8-9).

FIG. 8 is a graph illustrating the in vivo release profile ofbupivacaine obtained from depot formulations of the present invention(formulations 9-10).

FIG. 9 is a graph illustrating the in vivo release profile ofbupivacaine obtained from depot formulations of the present invention(formulations 10-11).

FIG. 10 is a graph illustrating the in vivo release profile ofbupivacaine obtained from depot formulations of the present invention(formulations 11-12).

FIG. 11 is a DSC diagram of the low molecular weight PLGA with an esterend group used to make various formulations of the present invention(formulations 2, 4, 6, 7, 11, and 12).

FIG. 12 is a DSC diagram of the low molecular weight PLGA with acarboxyl end group used to make a various formulations of the presentinvention (formulations 8, 9, and 10).

FIG. 13 is a graph illustrating the in vitro degradation profile of PLGApolymers of varying molecular weights with different end groups.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to an injectable depot compositionthat serves as an implanted sustained release beneficial agent deliverysystem after injection into a patient's body. The composition is a gelformed from a low molecular weight bioerodible, biocompatible polymer; asolvent having a miscibility in water of less than or equal to 7 wt. %at 25° C., in an amount effective to plasticize the polymer and form agel therewith; and a beneficial agent dissolved or dispersed in the gel.The present invention is also directed to a method of systemically orlocally administering a beneficial agent to a subject by implanting inthe subject an injectable depot composition as described above. Byappropriate choice of solvent, water migration from the aqueousenvironment surrounding the implant system is restricted, and beneficialagent is released to the subject over a period of time, thus providingfor delivery of the beneficial agent with a controlled burst ofbeneficial agent and sustained release thereafter. The duration and therate of release of the beneficial agent are controlled by appropriatechoice of the low molecular weight biodegradable polymer. Thecomposition provides controlled sustained release of the beneficialagent by restricting water migration from the aqueous environmentsurrounding the implant system, thus delivering the beneficial agentover a short duration, preferably a period equal to or less than twoweeks, preferably about 24 hours to about 2 weeks, preferably about 10days or shorter; preferably about 7 days or shorter, more preferablyabout 3 days to about 7 days. Because the polymer of the composition isbioerodible, the implant system does not have to be surgically removedafter beneficial agent is depleted from the implant.

Generally, the compositions of the invention are gel-like and faun witha substantially homogeneous non-porous structure throughout the implantupon implantation and during drug delivery, even as it hardens.Furthermore, while the polymer gel implant will slowly harden whensubjected to an aqueous environment, the hardened implant may maintain arubbery (non-rigid) composition with the glass transition temperatureT_(g) being below 37° C.

It has been discovered that when a solvent having a solubility in waterof less than 7% by weight in water is present in the system, suitableburst control and sustained delivery of beneficial agent is achieved,whether or not a solubility modulator of the beneficial agent is presentin the system. Typically, the implant systems useful in this inventionwill release, in the first 24 hours after implantation, 40% or less ofthe total amount of beneficial agent to be delivered to the subject fromthe implant system, preferably 30% or less and more preferably 20% orless. In certain embodiments, within 24 hours after implantation thesystem releases less than or equal to 20% by weight of the amount ofbeneficial agent to be delivered over the duration of the deliveryperiod, wherein the delivery period is 2 weeks. In additionalembodiments, within 24 hours after implantation the system releases lessthan or equal to 40% by weight of the amount of beneficial agent to bedelivered over the duration of the delivery period, wherein the deliveryperiod is one week. In additional embodiments, within 24 hours afterimplantation the system releases less than or equal to 50% by weight ofthe amount of beneficial agent to be delivered over the duration of thedelivery period, wherein the delivery period is three days.

When the composition is intended for implantation by injection, theviscosity optionally may be modified by emulsifiers and/or thixotropicagents to obtain a gel composition having a viscosity low enough topermit passage of the gel composition through a needle. Also, poreformers and solubility modulators of the beneficial agent may be addedto the implant systems to provide desired release profiles from theimplant systems, along with typical pharmaceutical excipients and otheradditives that do not change the beneficial aspects of the presentinvention. The addition of a solubility modulator to the implant systemmay enable the use of a solvent having a solubility of 7% or greater inthe implant system with minimal burst and sustained delivery underparticular circumstances. However, it is presently preferred that theimplant system utilize at least one solvent having a solubility in waterof less than 7% by weight, whether the solvent is present alone or aspart of a solvent mixture. It has also been discovered that whenmixtures of solvents which include a solvent having 7% or less by weightsolubility in water and one or more miscible solvents, optionally havinggreater solubility, are used, implant systems exhibiting limited wateruptake and minimal burst and sustained delivery characteristics areobtained.

Definitions

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a solvent” includes a single solvent as well as a mixture of two ormore different solvents, reference to “a beneficial agent” includes asingle beneficial agent as well as two or more different beneficialagents in combination, and the like.

The term “beneficial agent” means an agent that effects a desiredbeneficial, often pharmacological, effect upon administration to a humanor an animal, whether alone or in combination with other pharmaceuticalexcipients or inert ingredients.

As used herein, the term “polynucleotide” refers to a polymeric form ofnucleotides of any length, either ribonucleotides ordeoxyribonucleotides, and includes double- and single-stranded DNA andRNA. It also includes known types of modifications, substitutions, andinternucleotide modifications, which are known in the art.

As used herein, the term “recombinant polynucleotide” refers to apolynucleotide of genomic, cDNA, semisynthetic, or synthetic originwhich, by virtue of its origin or manipulation: is not associated withall or a portion of a polynucleotide with which it is associated innature; is linked to a polynucleotide other than that to which it islinked in nature; or does not occur in nature.

As used herein, the term “polypeptide” refers to a polymer of aminoacids, including for example, peptides, oligopeptides, and proteins andderivatives, analogs and fragments thereof, as well as othermodifications known in the art, both naturally occurring andnon-naturally occurring.

As used herein, the term “purified” and “isolated” when referring to apolypeptide or nucleotide sequence means that the indicated molecule ispresent in the substantial absence of other biological macromolecules ofthe same type. The term “purified” as used herein preferably means atleast 75% by weight, more preferably at least 85% by weight, morepreferably still at least 95% by weight, and most preferably at least98% by weight, of biological macromolecules of the same type present.

The term “AUC” means the area under the curve obtained from an in vivoassay in a subject by plotting blood plasma concentration of thebeneficial agent in the subject against time, as measured from the timeof implantation of the composition, to a time “t” after implantation.The time t will correspond to the delivery period of beneficial agent toa subject.

The term “burst index” means, with respect to a particular compositionintended for systemic delivery of a beneficial agent, the quotientformed by dividing (i) the AUC calculated for the first time periodafter implantation of the composition into a subject divided by thenumber of hours in the first time period (t₁), by (ii) the AUCcalculated for the time period of delivery of beneficial agent, dividedby the number of hours in the total duration of the delivery period(t₂). For example the burst index at 24 hours is the quotient formed bydividing (i) the AUC calculated for the first twenty-four hours afterimplantation of the composition into a subject divided by the number 24,by (ii) the AUC calculated for the time period of delivery of beneficialagent, divided by the number of hours in the total duration of thedelivery period.

The phrase “dissolved or dispersed” is intended to encompass all meansof establishing a presence of beneficial agent in the gel compositionand includes dissolution, dispersion, suspension and the like.

The term “systemic” means, with respect to delivery or administration ofa beneficial agent to a subject, that the beneficial agent is detectableat a biologically-significant level in the blood plasma of the subject.

The term “local” means, with respect to delivery or administration of abeneficial agent to a subject, that the beneficial agent is delivered toa localized site in the subject but is not detectable at a biologicallysignificant level in the blood plasma of the subject.

The terms “short period” or “short duration” are used interchangeablyand refer to a period of time over which release of a beneficial agentfrom the depot gel composition of the invention occurs, which willgenerally be equal to or less than two weeks, preferably about 24 hoursto about 2 weeks, preferably about 10 days or shorter; preferably about7 days or shorter, more preferably about 3 days to about 7 days.

The term “gel vehicle” means the composition formed by mixture of thepolymer and solvent in the absence of the beneficial agent.

The term “initial burst” means, with respect to a particular compositionof this invention, the quotient obtained by dividing (i) the amount byweight of beneficial agent released from the composition in apredetermined initial period of time after implantation, by (ii) thetotal amount of beneficial agent that is to be delivered from animplanted composition. It is understood that the initial burst may varydepending on the shape and surface area of the implant. Accordingly, thepercentages and burst indices associated with initial burst describedherein are intended to apply to compositions tested in a form resultingfrom dispensing of the composition from a standard syringe.

The term “solubility modulator” means, with respect to the beneficialagent, an agent that will alter the solubility of the beneficial agent,with reference to polymer solvent or water, from the solubility ofbeneficial agent in the absence of the modulator. The modulator mayenhance or retard the solubility of the beneficial agent in the solventor water. However, in the case of beneficial agents that are highlywater soluble, the solubility modulator will generally be an agent thatwill retard the solubility of the beneficial agent in water. The effectsof solubility modulators of the beneficial agent may result frominteraction of the solubility modulator with the solvent, or with thebeneficial agent itself, such as by the formation of complexes, or withboth. For the purposes hereof, when the solubility modulator is“associated” with the beneficial agent, all such interactions orformations as may occur are intended. Solubility modulators may be mixedwith the beneficial agent prior to its combination with the viscous gelor may be added to the viscous gel prior to the addition of thebeneficial agent, as appropriate.

The terms “subject” and “patient” mean, with respect to theadministration of a composition of the invention, an animal or a humanbeing.

Since all solvents, at least on a molecular level, will be soluble inwater (i.e., miscible with water) to some very limited extent, the term“immiscible” as used herein means that 7% or less by weight, preferably5% or less, of the solvent is soluble in or miscible with water. For thepurposes of this disclosure, solubility values of solvent in water areconsidered to be determined at 25° C. Since it is generally recognizedthat solubility values as reported may not always be conducted at thesame conditions, solubility limits recited herein as percent by weightmiscible or soluble with water as part of a range or upper limit may notbe absolute. For example, if the upper limit on solvent solubility inwater is recited herein as “7% by weight,” and no further limitations onthe solvent are provided, the solvent “triacetin,” which has a reportedsolubility in water of 7.17 grams in 100 ml of water, is considered tobe included within the limit of 7%. A solubility limit in water of lessthan 7% by weight as used herein does not include the solvent triacetinor solvents having solubilities in water equal to or greater thantriacetin.

The term “bioerodible” refers to a material that gradually decomposes,dissolves, hydrolyzes and/or erodes in situ. Generally, the“bioerodible” polymers herein are polymers that are hydrolyzable, andbioerode in situ primarily through hydrolysis.

The term “thixotropic” is used in its conventional sense to refer to agel composition that can liquefy or at least exhibit a decrease inapparent viscosity upon application of mechanical force such as shearforce. The extent of the reduction is in part a function of the shearrate of the gel when subjected to the shearing force. When the shearingforce is removed, the viscosity of the thixotropic gel returns to aviscosity at or near that which it displayed prior to being subjected tothe shearing force. Accordingly, a thixotropic gel may be subjected to ashearing force when injected from a syringe which temporarily reducesits viscosity during the injection process. When the injection processis completed, the shearing force is removed and the gel returns verynear to its previous state.

A “thixotropic agent” as used herein is one that increases thethixotropy of the composition in which it is contained, promoting shearthinning and enabling use of reduced injection force.

The term “low molecular weight (LMW) polymer” refers to bioerodiblepolymers having a weight average molecular weight ranging from about3000 to about 10,000; preferably from about 3000 to about 9,000; morepreferably from about 4000 to about 8,000; and more preferably the lowmolecular weight polymer has a molecular weight of about 7000, about6000, about 5000, about 4000 and about 3000 as determined by gelpermeation chromatography (GPC).

The term “high molecular weight (HMW) polymer” refers to bioerodiblepolymers having a weight average molecular weight greater than 10,000 asdetermined by gel permeation chromatography (GPC).

The polymer, solvent and other agents of the invention must be“biocompatible”; that is they must not cause irritation, inflammation ornecrosis in the environment of use. The environment of use is a fluidenvironment and may comprise a subcutaneous, intramuscular,intravascular (high/low flow), intramyocardial, adventitial,intratumoral, or intracerebral portion, wound sites, tight joint spacesor body cavity of a human or animal.

The following definitions apply to the molecular structures describedherein:

As used herein, the phrase “having the formula” or “having thestructure” is not intended to be limiting and is used in the same waythat the term “comprising” is commonly used.

The term “alkyl” as used herein refers to a saturated hydrocarbon grouptypically although not necessarily containing 1 to about 30 carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups suchas cyclopentyl, cyclohexyl and the like. Generally, although again notnecessarily, alkyl groups herein contain 1 to about 12 carbon atoms. Theterm “lower alkyl” intends an alkyl group of 1 to 6 carbon atoms,preferably 1 to 4 carbon atoms. “Substituted alkyl” refers to alkylsubstituted with one or more substituent groups, and the terms“heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in whichat least one carbon atom is replaced with a heteroatom. If not otherwiseindicated, the terms “alkyl” and “lower alkyl” include linear, branched,cyclic, unsubstituted, substituted, and/or heteroatom-containing alkylor lower alkyl.

The term “aryl” as used herein, and unless otherwise specified, refersto an aromatic substituent containing a single aromatic ring or multiplearomatic rings that are fused together, linked covalently, or linked toa common group such as a methylene or ethylene moiety. Preferred arylgroups contain one aromatic ring or two fused or linked aromatic rings,e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine,benzophenone, and the like, and most preferred aryl groups aremonocyclic. “Substituted aryl” refers to an aryl moiety substituted withone or more substituent groups, and the terms “heteroatom-containingaryl” and “heteroaryl” refer to aryl in which at least one carbon atomis replaced with a heteroatom. Unless otherwise indicated, the term“aryl” includes heteroaryl, substituted aryl, and substituted heteroarylgroups.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup, wherein alkyl and aryl are as defined above. The term“heteroaralkyl” refers to an alkyl group substituted with a heteroarylgroup. Unless otherwise indicated, the term “aralkyl” includesheteroaralkyl and substituted aralkyl groups as well as unsubstitutedaralkyl groups. Generally, the term “aralkyl” herein refers to anaryl-substituted lower alkyl group, preferably a phenyl substitutedlower alkyl group such as benzyl, phenethyl, 1-phenylpropyl,2-phenylpropyl, and the like.

The term “heteroatom-containing” as in a “heteroatom-containinghydrocarbyl group” refers to a molecule or molecular fragment in whichone or more carbon atoms is replaced with an atom other than carbon,e.g., nitrogen, oxygen, sulfur, phosphorus or silicon. Similarly, theterm “heterocyclic” refers to a cyclic substituent that isheteroatom-containing, the term “heteroaryl” refers to an arylsubstituent that is heteroatom-containing, and the like.

By “substituted” as in “substituted alkyl,” “substituted aryl” and thelike, as alluded to in some of the aforementioned definitions, is meantthat in the alkyl or aryl moiety, respectively, at least one hydrogenatom bound to a carbon atom is replaced with one or more non-interferingsubstituents such as hydroxyl, alkoxy, thio, amino, halo, and the like.

I. Injectable Depot Compositions:

As described previously, injectable depot compositions for delivery ofbeneficial agents over a short duration of time may be formed as viscousgels prior to injection of the depot into a subject. The viscous gelsupports dispersed beneficial agent to provide appropriate deliveryprofiles, which include those having low initial burst, of thebeneficial agent as the beneficial agent is released from the depot overtime.

The polymer, solvent and other agents of the invention must bebiocompatible; that is they must not cause irritation or necrosis in theenvironment of use. The environment of use is a fluid environment andmay comprise a subcutaneous, intramuscular, intravascular (high/lowflow), intramyocardial, adventitial, intratumoral, or intracerebralportion, wound sites, tight joint spaces or body cavity of a human oranimal. In certain embodiments, the beneficial agent may be administeredlocally to avoid or minimize systemic side effects. Gels of the presentinvention containing a beneficial agent may be injected/implanteddirectly into or applied as a coating to the desired location, e.g.,subcutaneous, intramuscular, intravascular, intramyocardial,adventitial, intratumoral, or intracerebral portion, wound sites, tightjoint spaces or body cavity of a human or animal.

Typically, the viscous gel will be injected from a standard hypodermicsyringe, a catheter or a trocar, that has been pre-filled with thebeneficial agent-viscous gel composition as the depot. It is oftenpreferred that injections take place using the smallest size needle(i.e., smallest diameter) or catheter to reduce discomfort to thesubject when the injection is in a subcutaneous, intramuscular,intravascular (high/low flow), intramyocardial, adventitial,intratumoral, or intracerebral portion, wound sites, tight joint spacesor body cavity of a human or animal. It is desirable to be able toinject gels through a needle or a catheter ranging from 16 gauge andhigher, preferably 20 gauge and higher, more preferably 22 gauge andhigher, even more preferably 24 gauge and higher. With highly viscousgels, i.e., gels having a viscosity of about 100 poise or greater,injection forces to dispense the gel from a syringe having a needle inthe 20-30 gauge range may be so high as to make the injection difficultor reasonably impossible when done manually. At the same time, the highviscosity of the gel is desirable to maintain the integrity of the depotafter injection and during the dispensing period and also facilitatedesired suspension characteristics of the beneficial agent in the gel.

A composition of a polymer and polymer solvent that optionally includesan agent that imparts thixotropic characteristics to the viscous gelformed by the polymer solvent and polymer provides certain advantages. Athixotropic gel exhibits reduced viscosity when subjected to shearforce. The extent of the reduction is in part a function of the shearrate of the gel when subjected to the shearing force. When the shearingforce is removed, the viscosity of the thixotropic gel returns to aviscosity at or near that which it displayed prior to being subjected tothe shearing force. Accordingly, a thixotropic gel may be subjected to ashearing force when injected from a syringe or a catheter, whichtemporarily reduces its viscosity during the injection process. When theinjection process is completed, the shearing force is removed and thegel returns very near to its previous state.

Significant shear thinning properties of the injectable compositionallow for a minimally invasive delivery, via a needle or a catheter, ofa beneficial agent to various sites on an external and/or internalsurface of the body. Further injection through the needle or injectioncatheter permits precise administration of a desirable amount of thecomposition at a desired location, with significant retention of thedepot gel composition at the site of delivery while providing forsustained delivery of the beneficial agent from the site ofadministration. In certain embodiments, the injection catheter mayinclude a metering device or an additional device to assist in theprecise delivery of the composition.

A. The Bioerodible, Biocompatible Polymer:

Polymers that are useful in conjunction with the methods andcompositions of the invention are bioerodible, i.e., they graduallydegrade e.g., enzymatically or hydrolyze, dissolve, physically erode, orotherwise disintegrate within the aqueous fluids of a patient's body.Generally, the polymers bioerode as a result of hydrolysis or physicalerosion, although the primary bioerosion process is typically hydrolysisor enzymatic degradation.

Such polymers include, but are not limited to polylactides,polyglycolides, polyanhydrides, polyamines, polyesteramides,polyorthoesters, polydioxanones, polyacetals, polyketals,polycarbonates, polyorthocarbonates, polyphosphazenes, succinates,poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethyleneglycol, polyhydroxycellulose, polyphosphoesters, chitin, chitosan,hylauronic acid and copolymers, terpolymers and mixtures thereof.

The low molecular weight bioerodible polymers have weight averagemolecular weight ranging from about 3000 to about 10,000; preferablyfrom about 3000 to about 9,000; more preferably from about 4000 to about8,000; and more preferably the low molecular weight polymer has amolecular weight of about 7000, about 6000, about 5000, about 4000 andabout 3000 as determined by gel permeation chromatography (GPC).

Presently preferred polymers are polylactides, that is, a lacticacid-based polymer that can be based solely on lactic acid or can be acopolymer based on lactic acid and glycolic acid which may include smallamounts of other comonomers that do not substantially affect theadvantageous results which can be achieved in accordance with thepresent invention. As used herein, the term “lactic acid” includes theisomers L-lactic acid, D-lactic acid, DL-lactic acid and lactide whilethe term “glycolic acid” includes glycolide. Most preferred arepoly(lactide-co-glycolide)copolymers, commonly referred to as PLGA. Thepolymer may have a monomer ratio of lactic acid/glycolic acid of fromabout 100:0 to about 15:85, preferably from about 60:40 to about 75:25and an especially useful copolymer has a monomer ratio of lacticacid/glycolic acid of about 50:50.

The lactic acid-based polymer has a weight average molecular weightranging from about 3000 to about 10,000; preferably from about 3000 toabout 9,000; more preferably from about 4000 to about 8,000; and morepreferably the low molecular weight polymer has a molecular weight ofabout 7000, about 6000, about 5000, about 4000 and about 3000 asdetermined by gel permeation chromatography (GPC). As indicated inaforementioned U.S. Pat. No. 5,242,910, the polymer can be prepared inaccordance with the teachings of U.S. Pat. No. 4,443,340. Alternatively,the lactic acid-based polymer can be prepared directly from lactic acidor a mixture of lactic acid and glycolic acid (with or without a furthercomonomer) in accordance with the techniques set forth in U.S. Pat. No.5,310,865. The contents of all of these patents are incorporated byreference. Suitable lactic acid-based polymers are availablecommercially. For instance, 50:50 lactic acid:glycolic acid copolymershaving weight average molecular weight ranging from about 3000 to about10,000; preferably from about 3000 to about 9,000; more preferably fromabout 4000 to about 8,000; and more preferably the low molecular weightpolymer has a molecular weight of about 7000, about 6000, about 5000,about 4000 and about 3000, and a wide variety of end groups to altersusceptibility to hydrolysis and subsequent breakdown of the polymerchain are available from Boehringer Ingelheim (Petersburg, Va.).

Examples of polymers include, but are not limited to, Poly(D,L-lactide-co-glycolide) 50:50 Resomer® RG502, code 0000366, Poly(D,L-lactide-co-glycolide) 50:50 Resomer® RG502H, PLGA-502H, code no.260187, Poly D,L Lactide (Resomer® R 202, Resomer® R 203); Polydioxanone (Resomer® X 210) (Boehringer Ingelheim Chemicals, Inc.,Petersburg, Va.).

Additional examples include, but are not limited to,DL-lactide/glycolide 100:0 (MEDISORB® Polymer 100 DL High, MEDISORB®Polymer 100 DL Low); DL-lactide/glycolide 85/15 (MEDISORB® Polymer 8515DL High, MEDISORB® Polymer 8515 DL Low); DL-lactide/glycolide 75/25(MEDISORB® Polymer 7525 DL High, MEDISORB® Polymer 7525 DL Low);DL-lactide/glycolide 65/35 (MEDISORB® Polymer 6535 DL High, MEDISORB®Polymer 6535 DL Low); DL-lactide/glycolide 54/46 (MEDISORB® Polymer 5050DL High, MEDISORB® Polymer 5050 DL Low); and DL-lactide/glycolide 54/46(MEDISORB® Polymer 5050 DL 2A(3), MEDISORB® Polymer 5050 DL 3A(3),MEDISORB® Polymer 5050 DL 4A(3)) (Medisorb Technologies InternationalL.P., Cincinnati, Ohio); and Poly D,L-lactide-co-glycolide 50:50; PolyD,L-lactide-co-glycolide 65:35; Poly D,L-lactide-co-glycolide 75:25;Poly D,L-lactide-co-glycolide 85:15; Poly DL-lactide; Poly L-lactide;Poly glycolide; Poly ε-caprolactone; Poly DL-lacticle-co-caprolactone25:75; and Poly DL-lactide-co-caprolactone 75:25 (Birmingham Polymers,Inc., Birmingham, Ala.).

It has been surprisingly found that injectable depot gel formulations ofthe invention comprising low molecular weight polymers provide acontrolled, sustained release of a beneficial agent over a shortduration of time equal to or less than two weeks. The release rateprofile can be controlled by the appropriate choice of a low molecularweight polymer, a water immiscible solvent, the polymer/solvent ratio,emulsifying agent, thixotropic agent, pore former, solubility modifierfor the beneficial agent, an osmotic agent, and the like

The biocompatible polymer is present in the gel composition in an amountranging from about 5 to about 90% by weight, preferably from about 10 toabout 85% by weight, preferably from about 15 to about 80% by weight,preferably from about 20 to about 75% by weight, preferably from about30 to about 70% by weight and typically from about 35 to about 65%, andoften about 40 to about 60% by weight of the viscous gel, the viscousgel comprising the combined amounts of the biocompatible polymer and thesolvent. The solvent will be added to polymer in amounts describedbelow, to provide injectable depot gel compositions.

B. Solvents and Agents:

The injectable depot composition of the invention contains awater-immiscible solvent in addition to the bioerodible polymer and thebeneficial agent. In preferred embodiments, the compositions describedherein are also free of solvents having a miscibility in water that isgreater than 7 wt. % at 25° C.

The solvent must be biocompatible, should form a viscous gel with thepolymer, and restrict water uptake into the implant. The solvent may bea single solvent or a mixture of solvents exhibiting the foregoingproperties. The term “solvent”, unless specifically indicated otherwise,means a single solvent or a mixture of solvents. Suitable solvents willsubstantially restrict the uptake of water by the implant and may becharacterized as immiscible in water, i.e., having a solubility in waterof less than 7% by weight. Preferably, the solvents are five weightpercent or less soluble in water; more preferably three weight percentor less soluble in water; and even more preferably one weight percent orless soluble in water. Most preferably the solubility of the solvent inwater is equal to or less than 0.5 weight percent.

Water miscibility may be determined experimentally as follows: Water(1-5 g) is placed in a tared clear container at a controlledtemperature, about 20° C., and weighed, and a candidate solvent is addeddropwise. The solution is swirled to observe phase separation. When thesaturation point appears to be reached, as determined by observation ofphase separation, the solution is allowed to stand overnight and isre-checked the following day. If the solution is still saturated, asdetermined by observation of phase separation, then the percent (w/w) ofsolvent added is determined. Otherwise more solvent is added and theprocess repeated. Solubility or miscibility is determined by dividingthe total weight of solvent added by the final weight of thesolvent/water mixture. When solvent mixtures are used, for example 20%triacetin and 80% benzyl benzoate, they are pre-mixed prior to adding tothe water.

Solvents useful in this invention are generally less than 7% watersoluble by weight as described above. Solvents having the abovesolubility parameter may be selected from aromatic alcohols, the loweralkyl and aralkyl esters of aryl acids such as benzoic acid, thephthalic acids, salicylic acid, lower alkyl esters of citric acid, suchas triethyl citrate and tributyl citrate and the like, and aryl, aralkyland lower alkyl ketones. Among preferred solvents are those havingsolubilities within the foregoing range selected from compounds havingthe following structural formulas (I), (II) and (III).

The aromatic alcohol has the structural formula (I)Ar-(L)_(n)-OH  (I)

wherein Ar is a substituted or unsubstituted aryl or heteroaryl group, nis zero or 1, and L is a linking moiety. Preferably, Ar is a monocyclicaryl or heteroaryl group, optionally substituted with one or morenoninterfering substituents such as hydroxyl, alkoxy, thio, amino, halo,and the like. More preferably, Ar is an unsubstituted 5- or 6-memberedaryl or heteroaryl group such as phenyl, cyclopentadienyl, pyridinyl,pyrimadinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl,thiophenyl, thiazolyl, isothiazolyl, or the like. The subscript “n” iszero or 1, meaning that the linking moiety L may or may not be present.Preferably, n is 1 and L is generally a lower alkylene linkage such asmethylene or ethylene, wherein the linkage may include heteroatoms suchas O, N or S. Most preferably, Ar is phenyl, n is 1, and L is methylene,such that the aromatic alcohol is benzyl alcohol.

The aromatic acid ester or ketone may be selected from the lower alkyland aralkyl esters of aromatic acids, and aryl and aralkyl ketones.Generally, although not necessarily, the aromatic acid esters andketones will respectively have the structural formula (II) or (III)

In the ester of formula (II), R¹ is substituted or unsubstituted aryl,aralkyl, heteroaryl or heteroaralkyl, preferably substituted orunsubstituted aryl or heteroaryl, more preferably monocyclic or bicyclicaryl or heteroaryl optionally substituted with one or morenon-interfering substituents such as hydroxyl, carboxyl, alkoxy, thio,amino, halo, and the like, still more preferably 5- or 6-membered arylor heteroaryl such as phenyl, cyclopentadienyl, pyridinyl, pyrimadinyl,pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl,thiazolyl, or isothiazolyl, and most preferably 5- or 6-membered aryl.R² is hydrocarbyl or heteroatom-substituted hydrocarbyl, typically loweralkyl or substituted or unsubstituted aryl, aralkyl, heteroaryl orheteroaralkyl, preferably lower alkyl or substituted or unsubstitutedaralkyl or heteroaralkyl, more preferably lower alkyl or monocyclic orbicyclic aralkyl or heteroaralkyl optionally substituted with one ormore non-interfering substituents such as hydroxyl, carboxyl, alkoxy,thio, amino, halo, and the like, still more preferably lower alkyl or 5-or 6-membered aralkyl or heteroaralkyl, and most preferably lower alkylor 5- or 6-membered aryl optionally substituted with one or moreadditional ester groups having the structure —O—(CO)—R¹. Most preferredesters are benzoic acid and phthalic acid derivatives.

In the ketone of formula (III), R³ and R⁴ may be selected from any ofthe R¹ and R² groups identified above.

Art recognized benzoic acid derivatives from which solvents having therequisite solubility may be selected include, without limitation:1,4-cyclohexane dimethanol dibenzoate, diethylene glycol dibenzoate,dipropylene glycol dibenzoate, polypropylene glycol dibenzoate,propylene glycol dibenzoate, diethylene glycol benzoate and dipropyleneglycol benzoate blend, polyethylene glycol (200) dibenzoate, isodecylbenzoate, neopentyl glycol dibenzoate, glyceryl tribenzoate,pentaerylthritol tetrabenzoate, cumylphenyl benzoate, trimethylpentanediol dibenzoate.

Art recognized phthalic acid derivatives from which solvents having therequisite solubility may be selected include: Alkyl benzyl phthalate,bis-cumyl-phenyl isophthalate, dibutoxyethyl phthalate, dimethylphthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate,diisobutyl phthalate, butyl octyl phthalate, diisoheptyl phthalate,butyl octyl phthalate, diisononyl phthalate, nonyl undecyl phthalate,dioctyl phthalate, di-isooctyl phthalate, dicapryl phthalate, mixedalcohol phthalate, di-(2-ethylhexyl) phthalate, linear heptyl, nonyl,phthalate, linear heptyl, nonyl, undecyl phthalate, linear nonylphthalate, linear nonyl undecyl phthalate, linear dinonyl, didecylphthalate (diisodecyl phthalate), diundecyl phthalate, ditridecylphthalate, undecyldodecyl phthalate, decyltridecyl phthalate, blend(50/50) of dioctyl and didecyl phthalates, butyl benzyl phthalate, anddicyclohexyl phthalate.

Many of the solvents useful in the invention are available commercially(Aldrich Chemicals, Sigma Chemicals) or may be prepared by conventionalesterification of the respective arylalkanoic acids using acid halides,and optionally esterification catalysts, such as described in U.S. Pat.No. 5,556,905, which is incorporated herein by reference, and in thecase of ketones, oxidation of their respective secondary alcoholprecursors.

Preferred solvents include aromatic alcohols, the lower alkyl andaralkyl esters of the aryl acids described above. Representative acidsare benzoic acid and the phthalic acids, such as phthalic acid,isophthalic acid, and terephathalic acid. Most preferred solvents arebenzyl alcohol and derivatives of benzoic acid and include, but are notlimited to, methyl benzoate, ethyl benzoate, n-propyl benzoate,isopropyl benzoate, butyl benzoate, isobutyl benzoate, sec-butylbenzoate, tert-butyl benzoate, isoamyl benzoate and benzyl benzoate,with benzyl benzoate being most especially preferred.

The composition may also include, in addition to the water-immisciblesolvent(s), one or more additional miscible solvents (“componentsolvents”), provided that any such additional solvent is other than alower alkanol. Component solvents compatible and miscible with theprimary solvent(s) may have a higher miscibility with water and theresulting mixtures may still exhibit significant restriction of wateruptake into the implant. Such mixtures will be referred to as “componentsolvent mixtures.” Useful component solvent mixtures may exhibitsolubilities in water greater than the primary solvents themselves,typically between 0.1 weight percent and up to and including 50 weightpercent, preferably up to and including 30 weight percent, and mostpreferably up to an including 10 weight percent, without detrimentallyaffecting the restriction of water uptake exhibited by the implants ofthe invention.

Component solvents useful in component solvent mixtures are thosesolvents that are miscible with the primary solvent or solvent mixture,and include, but are not limited, to triacetin, diacetin, tributyrin,triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyltributyl citrate, triethylglycerides, triethyl phosphate, diethylphthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid,glylcerin, ethylene glycol, polyethylene glycol, octanol, ethyl lactate,propylene glycol, propylene carbonate, ethylene carbonate,butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone,2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methylethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,caprolactam, decyhnethylsulfoxide, oleic acid, and1-dodecylazacyclo-heptan-2-one, and mixtures thereof.

Preferred solvent mixtures are those in which benzyl benzoate is theprimary solvent, and mixtures formed of benzyl benzoate and eithertriacetin, tributyl citrate, triethyl citrate or N-methyl-2-pyrrolidone.Preferred mixtures are those in which benzyl benzoate is present byweight in an amount of 50% or more, more preferably 60% or more and mostpreferably 80% or more of the total amount of solvent present.Especially preferred mixtures are those of 80/20 mixtures by weight ofbenzyl benzoate/triacetin and benzyl benzoate/N-methyl-2-pyrrolidone. Inadditional embodiments, the preferred solvent is benzyl alcohol, andmixtures formed of benzyl alcohol and either benzyl benzoate or ethylbenzoate. Preferred mixtures of benzyl alcohol/benzyl benzoate andbenzyl alcohol/ethyl benzoate are 1/99 mixtures by weight; 20/80mixtures by weight; 30/70 mixtures by weight; 50/50 mixtures by weight;70/30 mixtures by weight; 80/20 mixtures by weight; 99/1 mixtures byweight. Especially preferred mixtures of benzyl alcohol/benzyl benzoateand benzyl alcohol/ethyl benzoate are 25/75 mixtures by weight and 75/25mixtures by weight.

In an especially preferred embodiment, the primary solvent is selectedfrom an aromatic alcohol and lower alkyl and aralkyl esters of benzoicacid and the polymer is a lactic-acid based polymer, most preferablyPLGA, having weight average molecular weight ranging from about 3000 toabout 10,000; preferably from about 3000 to about 9,000; more preferablyfrom about 4000 to about 8,000; and more preferably the low molecularweight polymer has a molecular weight of about 7000, about 6000, about5000, about 4000 and about 3000. Presently, the most preferred solventsare benzyl alcohol, benzyl benzoate and the lower alkyl esters ofbenzoic acid, e.g. ethyl benzoate. The primary solvents, e.g., aromaticalcohol and benzoic acid esters may be used alone or in a mixture withother miscible solvents, e.g., triacetin, as described herein.

The solvent or solvent mixture is capable of dissolving the polymer toform a viscous gel that can maintain particles of the beneficial agentdissolved or dispersed and isolated from the environment of use prior torelease. The compositions of the present invention provide implantsuseful both for systemic and local administration of beneficial agent,the implants having a low burst index. Water uptake is controlled by theuse of a solvent or component solvent mixture that solublizes orplasticizes the polymer but substantially restricts uptake of water intoimplant. Additionally, the preferred compositions may provide viscousgels that have a glass transition temperature that is less than 37° C.,such that the gel remains non-rigid for a period of time afterimplantation of 24 hours or more.

The importance of restriction of water uptake and the appropriate choiceof a low molecular weight polymer and a water immiscible solvent for acontrolled, sustained delivery over a short duration can be appreciatedby reference to FIGS. 1-10 illustrating in vivo release rate profilesfor various compositions as a function of time.

The solvent or solvent mixture is typically present in an amount of fromabout 95 to about 10% by weight, preferably from about 80 to about 20%by weight, preferably about 75 to about 15% by weight, preferably fromabout 70 to about 20% by weight, preferably about 65 to about 20% byweight, preferably about 65 to about 30% by weight and often about 60 toabout 40% by weight of the viscous gel, i.e., the combined amounts ofthe polymer and the solvent. The polymer to solvent ratio ranges fromabout 30:70 to about 90:10 by weight; preferably about 40:60 to about80:20 by weight; preferably about 50:50 to about 75:25 by weight; andmore preferably about 55:45 to about 65:35 by weight.

In addition to the control of water uptake and associated initial burstby choice of solvent, agents that modulate the water solubility of thebeneficial agent can also be utilized in conjunction with the preferredsolvents to control burst of beneficial agent from the implant. Burstindices and percent of beneficial agent released in the firsttwenty-four hours after implantation may be reduced by one-third totwo-thirds or more by the use of solubility modulators associated withthe beneficial agent. Such modulators are typically coatings, substancesthat form complexes or otherwise associate with or stabilize thebeneficial agent such as metallic ions, other stabilizing agents, waxes,lipids, oils, non-polar emulsions, and the like. Use of such solubilitymodulators may permit the use of more highly water soluble solvents ormixtures and achieve burst indices of 8 or less for systemicapplications, or with respect to local applications, release ofbeneficial agent in the first 24 hours after implantation of not greaterthan 40% of the beneficial agent administered. Preferably that releasewill be not greater than 30% and more preferably not greater than 20%.

Limited water uptake by the compositions of this invention can oftenprovide the opportunity to prepare compositions without solubilitymodulators when in other compositions such modulators would benecessary.

In instances where the choice of solvent and polymer result incompositions severely restricting water uptake by themselves, it may bedesirable to add osmotic agents or other agents and hydroattractantsthat facilitate water uptake to desired levels. Such agents may be, forexample, sugars and the like, and are well known in the art.

Limited water uptake by the solvent-polymer compositions of the presentinvention results in the implant compositions being formed without thefinger-like pores in the surface of implants formed using prior artprocesses. Typically, a composition of the present invention takes theform of a substantially, homogeneous, sponge-like gel, with the pores inthe interior of the implant being much the same as the pores on thesurface of the implant. Compositions of the present invention retaintheir gel-like consistency and administer a beneficial agent in acontrolled manner, at a sustained rate over a short duration of timethan do prior art devices. This is possible with the appropriate choiceof low molecular weight polymers and water immiscible solvents, andfurther since the injectable depot gel compositions of the presentinvention generally have a glass transition temperature, Tg, of lessthan body temperature of the subject, e.g. 37° C. for humans. Because ofthe immiscibility of the solvents that are useful in this invention withwater, water uptake by the implant is restricted and the pores that doform tend to resemble a closed cell structure without significantnumbers of larger pores or pores extending from the surface into theinterior of the implant being open at the surface of the implant.Furthermore, the surface pores offer only a limited opportunity forwater from body fluids to enter the implant immediately afterimplantation, thus controlling the burst effect. Since the compositionsoften will be highly viscous prior to implantation, when the compositionis intended for implantation by injection, the viscosity optionally maybe modified by the use of viscosity-reducing, miscible solvents or theuse of emulsifiers, or by heating to obtain a gel composition having aviscosity or shear resistance low enough to permit passage of the gelcomposition through a needle.

The limit on the amount of beneficial agent released in the first 24hours that is either desired or required will depend on circumstancessuch as the overall duration of the delivery period, the therapeuticwindow for the beneficial agent, potential adverse consequences due tooverdosing, cost of beneficial agent, and the type of effect desired,e.g., systemic or local. Preferably, 40% or less of the beneficial agentwill be released in the first 24 hours after implantation, where thepercentage is based on the total amount of beneficial agent to bedelivered over the duration of the delivery period. Typically, higherpercentages of release in the first 24 hours can be tolerated if theduration of the delivery period is relatively short, e.g., a periodequal to or less than two weeks, preferably about 10 days or shorter;preferably about 7 days or shorter, more preferably about 3 days toabout 7 days, or if the beneficial agent has a wide therapeutic windowwith little likelihood of side effects, or if the beneficial agent actslocally. In certain embodiments, within 24 hours after implantation thesystem releases less than or equal to 20% by weight of the amount ofbeneficial agent to be delivered over the duration of the deliveryperiod, wherein the delivery period is 2 weeks. In additionalembodiments, within 24 hours after implantation the system releases lessthan or equal to 40% by weight of the amount of beneficial agent to bedelivered over the duration of the delivery period, wherein the deliveryperiod is one week. In additional embodiments, within 24 hours afterimplantation the system releases less than or equal to 50% by weight ofthe amount of beneficial agent to be delivered over the duration of thedelivery period, wherein the delivery period is three days.

Depending on the particular solvent or solvent mixture selected, thepolymer and beneficial agent, and optionally solubility modulators ofthe beneficial agent, the compositions of the present invention intendedfor systemic delivery may provide a gel composition having a burst indexof 8 or less, preferably 6 or less, more preferably 4 or less and mostpreferably 2 or less. Compositions of PLGA weight average molecularweight ranging from about 3000 to about 10,000; preferably from about3000 to about 9,000; more preferably from about 4000 to about 8,000; andmore preferably the low molecular weight polymer has a molecular weightof about 7000, about 6000, about 5000, about 4000 and about 3000 withsolvents having a miscibility in water of less than 7% by weight,optionally combined with the other solvents, providing implants intendedfor systemic delivery of beneficial agent having a burst index of 10 orless, preferably 7 or less, more preferably 5 or less and mostpreferably 3 or less, are particularly advantageous. The use of solventmixtures as discussed herein can be particularly advantageous as a meansof providing sufficient plasticizing of the polymer to obtain viscousgel formation and at the same time meet the desired burst indices andpercentage release objectives of the compositions of the invention.

Compositions intended for local delivery of beneficial agent are forgedin the same manner as those intended for systemic use. However, becauselocal delivery of beneficial agent to a subject will not result indetectable plasma levels of beneficial agent, such systems have to becharacterized by a percentage of beneficial agent released in apredetermined initial period, rather than a burst index as definedherein. Most typically, that period will be the first 24 hours afterimplantation and the percentage will be equal to the amount by weight ofthe beneficial agent released in the period (e.g. 24 hours) divided bythe amount by weight of the beneficial agent intended to be delivered inthe duration of the delivery period; multiplied by the number 100.Compositions of the present invention will have initial bursts of 40% orless, preferably 30% or less, most preferably 20% or less, for mostapplications.

In many instances, it may be desirable to reduce the initial burst ofbeneficial agent during local administration to prevent adverse effects.For example, implants of the invention containing chemotherapeuticagents are suitable for direct injection into tumors. However, manychemotherapeutic agents may exhibit toxic side effects when administeredsystemically. Consequently, local administration into the tumor may bethe treatment method of choice. It is necessary, however, to avoidadministration of a large burst of the chemotherapeutic agent if it ispossible that such agent would enter the vascular or lymphatic systemswhere it may exhibit side affects. Accordingly; in such instances theimplantable systems of the present invention having limited burst asdescribed herein are advantageous.

The gel formed by mixing the polymer and the solvent typically exhibitsa viscosity of from about 100 to about 50,000 poise, preferably fromabout 500 to about 30,000 poise, more preferably from about 500 to about10,000 poise measured at a 1.0 sec-1 shear rate and 25° C. using a HaakeRheometer at about 1-2 days after mixing is completed. Mixing thepolymer with the solvent can be achieved with conventional low shearequipment such as a Ross double planetary mixer for from about 10minutes to about 1 hour, although shorter and longer periods may bechosen by one skilled in the art depending on the particular physicalcharacteristics of the composition being prepared. Since the depot gelcomposition of the invention are administered as an injectablecomposition, a countervailing consideration when forming depot gelcompositions that are viscous gels is that thepolymer/solvent/beneficial agent composition have sufficiently lowviscosity in order to permit it to be forced through a small diameter,e.g., 18-20 gauge needle. If necessary, adjustment of viscosity of thegel for injection can be accomplished with emulsifying agents orthixotropic agents as described herein. Yet, such compositions shouldhave adequate dimensional stability so as to remain localized and beable to be removed if necessary. The particular gel or gel-likecompositions of the present invention satisfy such requirements.

If the polymer composition is to be administered as an injectable gel,the level of polymer dissolution will need to be balanced with theresulting gel viscosity, to permit a reasonable force to dispense theviscous gel from a needle, and the potential burst effect. Highlyviscous gels enable the beneficial agent to be delivered withoutexhibiting a significant burst effect, but may make it difficult todispense the gel through a needle. In those instances, an emulsifyingagent may optionally be added to the composition. Also, since theviscosity may generally be lowered as the temperature of the compositionincreases, it may be advantageous in certain applications to reduce theviscosity of the gel by heating to provide a more readily injectablecomposition. The shear thinning characteristics of the depot gelcompositions of the present invention allow them to be readily injectedinto an animal including humans using standard gauge needles withoutrequiring undue dispensing pressure.

When the emulsifying agent is mixed with the viscous gel formed from thepolymer and the solvent using conventional static or mechanical mixingdevices, such as an orifice mixer, the emulsifying agent forms aseparate phase composed of dispersed droplets of microscopic size thattypically have an average diameter of less than about 100 microns. Thecontinuous phase is formed of the polymer and the solvent. The particlesof the beneficial agent may be dissolved or dispersed in either thecontinuous phase or the droplet phase. In the resulting thixotropiccomposition, the droplets of emulsifying agent elongate in the directionof shear and substantially decrease the viscosity of the viscous gelformed from the polymer and the solvent. For instance, with a viscousgel having a viscosity of from about 5,000 to about 50,000 poisemeasured at 1.0 sec-1 at 25° C., one can obtain a reduction in viscosityto less than 100 poise when emulsified with a 10% ethanol/water solutionat 25° C. as determined by Haake Rheometer.

When used, the emulsifying agent typically is present in an amountranging from about 5 to about 80%, preferably from about 20 to about 60%and often 30 to 50% by weight based on the amount of the injectabledepot gel composition, that is the combined amounts of polymer, solvent,emulsifying agent and beneficial agent. Emulsifying agents include, forexample, solvents that are not fully miscible with the polymer solventor solvent mixture. Illustrative emulsifying agents are water, alcohols,polyols, esters, carboxylic acids, ketones, aldehydes and mixturesthereof. Preferred emulsifying agents are alcohols, propylene glycol,ethylene glycol, glycerol, water, and solutions and mixtures thereof.Especially preferred are water, ethanol, and isopropyl alcohol andsolutions and mixtures thereof. The type of emulsifying agent affectsthe size of the dispersed droplets. For instance, ethanol will providedroplets that have average diameters that can be on the order of tentimes larger than the droplets obtained with an isotonic saline solutioncontaining 0.9% by weight of sodium chloride at 21° C.

The thixotropic agent, i.e. an agent that imparts thixotropic propertiesto the polymer gel, is selected from the lower alkanols. Lower alkanolmeans an alcohol that contains 2-6 carbon atoms and is straight chain orbranched chain. Such alcohols may be exemplified by ethanol,isopropanol, and the like. Importantly, such a thixotropic agent is nota polymer solvent. (See e.g., Development of an in situ formingbidegradable poly-lactide-co-glycolide system for controlled release ofproteins, Lambert, W. J., and Peck, K. D., Journal of ControlledRelease, 33 (1995) 189-195). When used, the thixotropic agent may bepresent in amounts of 0.01 to 15 weight percent, preferably in amountsof 0.1 to 5 weight percent, and often in amounts of 0.5 to 5 weightpercent of the combined weight of the solvent and the thixotropic agent.

It is to be understood that the emulsifying agent and/or the thixotropicagent do not constitute a mere diluent or a polymer-solvent that reducesviscosity by simply decreasing the concentration of the components ofthe composition. The use of conventional diluents can reduce viscosity,but can also cause the burst effect mentioned previously when thediluted composition is injected. In contrast, the injectable depotcomposition of the present invention can be formulated to avoid theburst effect by selecting the appropriate low molecular weight polymer,the solvent and emulsifying agent so that once injected into place, theemulsifying agent has little impact on the release properties of theoriginal system.

Although the injectable depot gel composition of the present inventionpreferably are formed as viscous gels, the means of administration ofthe implants is not limited to injection, although that mode of deliverymay often be preferred. Where the injectable depot gel composition willbe administered as a leave-behind product, it may be formed to fit intoa body cavity existing after completion of surgery or it may be appliedas a flowable gel by brushing or palleting the gel onto residual tissueor bone. Such applications may permit loading of beneficial agent in thegel above concentrations typically present with injectable compositions.

Beneficial Agents:

The beneficial agent can be any physiologically or pharmacologicallyactive substance or substances optionally in combination withpharmaceutically acceptable carriers and additional ingredients such asantioxidants, stabilizing agents, permeation enhancers, etc. that do notsubstantially adversely affect the advantageous results that can beattained by the present invention. The beneficial agent may be any ofthe agents which are known to be delivered to the body of a human or ananimal and that are preferentially soluble in water rather than in thepolymer-dissolving solvent. These agents include drug agents,medicaments, vitamins, nutrients, or the like. Included among the typesof agents which meet this description are lower molecular weightcompounds, proteins, peptides, genetic material, nutrients, vitamins,food supplements, sex sterilants, fertility inhibitors and fertilitypromoters.

Drug agents which may be delivered by the present invention includedrugs which act on the peripheral nerves, adrenergic receptors,cholinergic receptors, the skeletal muscles, the cardiovascular system,smooth muscles, the blood circulatory system, synoptic sites,neuroeffector junctional sites, endocrine and hormone systems, theimmunological system, the reproductive system, the skeletal system,autacoid systems, the alimentary and excretory systems, the histaminesystem and the central nervous system. Suitable agents may be selectedfrom, for example, proteins, enzymes, hormones, polynucleotides,nucleoproteins, polysaccharides, glycoproteins, lipoproteins,polypeptides, steroids, analgesics, local anesthetics, antibioticagents, chemotherapeutic agents, immunosuppressive agents,anti-inflammatory agents including anti-inflammatory corticosteroids,antiproliferative agents, antimitotic agents, angiogenic agents,antipsychotic agents, central nervous system (CNS) agents,anticoagulants, fibrinolytic agents, growth factors, antibodies, oculardrugs, and metabolites, analogs (including synthetic and substitutedanalogs), derivatives (including aggregative conjugates/fusion withother macromolecules and covalent conjugates with unrelated chemicalmoieties by means known in the art) fragments, and purified, isolated,recombinant and chemically synthesized versions of these species.

Examples of drugs that may be delivered by the composition of thepresent invention include, but are not limited to, procaine, procainehydrochloride, tetracaine, tetracaine hydrochloride, cocaine, cocainehydrochloride, chloroprocaine, chloroprocaine hydrochloride,proparacaine, proparacaine hydrochloride, piperocaine, piperocainehydrochloride, hexylcaine, hexylcaine hydrochloride, naepaine, naepainehydrochloride, benzoxinate, benzoxinate hydrochloride, cyclomethylcaine,cyclomethylcaine hydrochloride, cyclomethylcaine sulfate, lidocaine,lidocaine hydrochloride, bupivicaine, bupivicaine hydrochloride,mepivicaine, mepivacaine hydrochloride, prilocaine, prilocainehydrochloride, dibucaine and dibucaine hydrochloride, etidocaine,benzocaine, propoxycaine, dyclonin, pramoxine, oxybuprocaine,prochlorperzine edisylate, ferrous sulfate, aminocaproic acid,mecamylamine hydrochloride, procainamide hydrochloride, amphetaminesulfate, methamphetamine hydrochloride, benzamphetamine hydrochloride,isoproterenol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperzine maleate, anisindone, diphenadione erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chloropromaide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, hydrocortisone, hydrocorticosteroneacetate, cortisone acetate, dexamethasone and its derivatives such asbetamethasone, triamcinolone, methyltestosterone, 17-S-estradiol,ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,17α-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, aspirin, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen,fenufen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic,difuinal, nimodipine, nitrendipine, nisoldipine, nicardipine,felodipine, lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine,lisinolpril, enalapril, enalaprilat, captopril, ramipril, famotidine,nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptyline, and imipramine. Furtherexamples are proteins and peptides which include, but are not limitedto, bone morphogenic proteins, insulin, colchicine, glucagon, thyroidstimulating hormone, parathyroid and pituitary hormones, calcitonin,renin, prolactin, corticotrophin, thyrotropic hormone, folliclestimulating hormone, chorionic gonadotropin, gonadotropin releasinghormone, bovine somatotropin, porcine somatotropin, oxytocin,vasopressin, GRF, somatostatin, lypressin, pancreozymin, luteinizinghormone, LHRH, LHRH agonists and antagonists, leuprolide, interferonssuch as interferon alpha-2a, interferon alpha-2b, and consensusinterferon, interleukins, growth factors such as epidermal growthfactors (EGF), platelet-derived growth factors (PDGF), fibroblast growthfactors (FGF), transforming growth factors-α (TGF-α), transforminggrowth factors-β (TGF-β), erythropoietin (EPO), insulin-like growthfactor-I (IGF-I), insulin-like growth factor-II (IGF-II), interleukin-1,interleukin-2, interleukin-6, interleukin-8, tumor necrosis factor-α(TNF-α), tumor necrosis factor-β (TNF-β), Interferon-α (INF-α),Interferon-β (INF-β), Interferon-γ (INF-γ), Interferon-ω (INF-ω), colonystimulating factors (CGF), vascular cell growth factor (VEGF),thrombopoietin (TPO), stromal cell-derived factors (SDF), placentagrowth factor (PlGF), hepatocyte growth factor (HGF), granulocytemacrophage colony stimulating factor (GM-CSF), glial-derived neurotropinfactor (GDNF), granulocyte colony stimulating factor (G-CSF), ciliaryneurotropic factor (CNTF), bone morphogeneic proteins (BMP), coagulationfactors, human pancreas hormone releasing factor, analogs andderivatives of these compounds, and pharmaceutically acceptable salts ofthese compounds, or their analogs or derivatives.

Additional examples of drugs that may be delivered by the composition ofthe present invention include, but are not limited to,antiproliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin, actinomycin D, daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas G(GP)II_(b)III_(a) inhibitors and vitronectin receptor antagonists;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine));platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);antipsychotic agents, (such as antipsychotic drugs, neuroleptic drugs,tranquillisers and antipsychotic agents binding to dopamine, histamine,muscarinic cholinergic, adrenergic and serotonin receptors, includingbut not limited to phenothiazines, thioxanthenes, butyrophenones,dibenzoxazepines, dibenzodiazepines and diphenylbutylpiperidines);central nervous system (CNS) agents; anticoagulants (heparin, syntheticheparin salts and other inhibitors of thrombin); fibrinolytic agents(such as tissue plasminogen activator, streptokinase and urokinase),aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab;antimigratory; antisecretory (breveldin); antiinflammatory: such asadrenocortical steroids (cortisol, cortisone, fludrocortisone,prednisone, prednisolone, 6α-methylprednisolone, triamcino tone,betamethasone, and dexamethasone), non-steroidal agents (salicylic acidderivatives i.e. aspirin; para-aminophenol derivatives i.e.acetominophen); indole and indene acetic acids (indomethacin, sulindac,and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, andketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilicacids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam,tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, goldcompounds (auranofin, aurothioglucose, gold sodium thiomalate);immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus(rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents:vascular endothelial growth factor (VEGF), fibroblast growth factor(FGF); angiotensin receptor blocker; nitric oxide donors; anti-senseoligionucleotides and combinations thereof; cell cycle inhibitors, mTORinhibitors, and growth factor signal transduction kinase inhibitors,analogs and derivatives of these compounds, and pharmaceuticallyacceptable salts of these compounds, or their analogs or derivatives.

In certain preferred embodiments, the beneficial agent includeschemotactic growth factors, proliferative growth factors, stimulatorygrowth factors, and transformational peptide growth factors includinggenes, precursors, post-translational-variants, metabolites,binding-proteins, receptors, receptor agonists and antagonists of thefollowing growth factor families: epidermal growth factors (EGFs),platelet-derived growth factor (PDGFs), growth factors (IGFs),fibroblast-growth factors (FGFs), transforming-growth factors (TGFs),interleukins (Ms), colony-stimulating factors (CSFs, MCFs, GCSFs,GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF, EGFs),erythropoietins (EPOs), angiopoietins (ANGs), placenta-derived growthfactors (PlGFs), and hypoxia induced transcriptional regulators (HTFs).

The present invention also finds application with chemotherapeuticagents for the local application of such agents to avoid or minimizesystemic side effects. Gels of the present invention containingchemotherapeutic agents may be injected directly into the tumor tissuefor sustained delivery of the chemotherapeutic agent over time. In somecases, particularly after resection of the tumor, the gel may beimplanted directly into the resulting cavity or may be applied to theremaining tissue as a coating. In cases in which the gel is implantedafter surgery, it is possible to utilize gels having higher viscositiessince they do not have to pass through a small diameter needle.Representative chemotherapeutic agents that may be delivered inaccordance with the practice of the present invention include, forexample, carboplatin, cisplatin, paclitaxel, BCNU, vincristine,camptothecin, etopside, cytokines, ribozymes, interferons,oligonucleotides and oligonucleotide sequences that inhibit translationor transcription of tumor genes, functional derivatives of theforegoing, and generally known chemotherapeutic agents such as thosedescribed in U.S. Pat. No. 5,651,986. The present application hasparticular utility in the sustained delivery of water solublechemotherapeutic agents, such as for example cisplatin and carboplatinand the water soluble derivatives of paclitaxel. Those characteristicsof the invention that minimize the burst effect are particularlyadvantageous in the administration of water soluble beneficial agents ofall kinds, but particularly those compounds that are clinically usefuland effective but may have adverse side effects.

To the extent not mentioned above, the beneficial agents described inaforementioned U.S. Pat. No. 5,242,910 can also be used. One particularadvantage of the present invention is that materials, such as proteins,as exemplified by the enzyme lysozyme, and cDNA, and DNA incorporatedinto vectors both viral and nonviral, which are difficult tomicroencapsulate or process into microspheres can be incorporated intothe compositions of the present invention without the level ofdegradation caused by exposure to high temperatures and denaturingsolvents often present in other processing techniques.

The beneficial agent is preferably incorporated into the viscous gelformed from the polymer and the solvent in the form of particlestypically having an average particle size of from about 0.1 to about 250microns, preferably from about 1 to about 200 microns and often from 30to 125 microns. For instance, particles having an average particle sizeof about 5 microns have been produced by spray drying or freeze dryingan aqueous mixture containing 50% sucrose and 50% chicken lysozyme (on adry weight basis) and mixtures of 10-20% hGH and 15-30 mM zinc acetate.Such particles have been used in certain of the examples illustrated inthe figures. Conventional Lyophilization processes can also be utilizedto form particles of beneficial agents of varying sizes usingappropriate freezing and drying cycles.

To form a suspension or dispersion of particles of the beneficial agentin the viscous gel formed from the polymer and the solvent, anyconventional low shear device can be used such as a Ross doubleplanetary mixer at ambient conditions. In this manner, efficientdistribution of the beneficial agent can be achieved substantiallywithout degrading the beneficial agent.

The beneficial agent is typically dissolved or dispersed in thecomposition in an amount of from about 0.1% to about 50% by weight,preferably in an amount of from about 1% to about 40%, more preferablyin an amount of about 2% to about 30%, and often 2 to 20% by weight ofthe combined amounts of the polymer, solvent, and beneficial agent.Depending on the amount of beneficial agent present in the composition,one can obtain different release profiles and burst indices. Morespecifically, for a given polymer and solvent, by adjusting the amountsof these components and the amount of the beneficial agent, one canobtain a release profile that depends more on the degradation of thepolymer than the diffusion of the beneficial agent from the compositionor vice versa. In this respect, at lower beneficial agent loading rates,one generally obtains a release profile reflecting degradation of thepolymer wherein the release rate increases with time. At higher loadingrates, one generally obtains a release profile caused by diffusion ofthe beneficial agent wherein the release rate decreases with time. Atintermediate loading rates, one obtains combined release profiles sothat if desired, a substantially constant release rate can be attained.In order to minimize burst, loading of beneficial agent on the order of30% or less by weight of the overall gel composition, i.e., polymer,solvent and beneficial agent, is preferred, and loading of 20% or lessis more preferred.

Release rates and loading of beneficial agent will be adjusted toprovide for therapeutically-effective delivery of the beneficial agentover the intended sustained delivery period. Preferably, the beneficialagent will be present in the polymer gel at concentrations that areabove the saturation concentration of beneficial agent in water toprovide a drug reservoir from which the beneficial agent is dispensed.While the release rate of beneficial agent depends on the particularcircumstances, such as the beneficial agent to be administered, releaserates on the order of from about 0.1 to about 100 micrograms/day,preferably from about 1 to about 10 micrograms per day, for periods offrom about 3 to about two weeks can be obtained. Greater amounts may bedelivered if delivery is to occur over shorter periods. Generally,higher release rate is possible if a greater burst can be tolerated. Ininstances where the gel composition is surgically implanted, or used asa “leave behind” depot when surgery to treat the disease state oranother condition is concurrently conducted, it is possible to providehigher doses that would normally be administered if the implant wasinjected. Further, the dose of beneficial agent may be controlled byadjusting the volume of the gel implanted or the injectable gelinjected.

FIGS. 1-9 illustrate representative release profiles of variousbeneficial agents obtained in rats from preferred compositions of thisinvention. As illustrated in the figures, the injectable depot gelformulations of the invention comprising low molecular weight polymersprovide a controlled, sustained release of a beneficial agent over ashort duration of time equal to or less than two weeks.

Optional Additional Components:

Other components may be present in the injectable depot gel composition,to the extent they are desired or provide useful properties to thecomposition, such as polyethylene glycol, hydroscopic agents,stabilizing agents, pore founding agents, and others. When thecomposition includes a peptide or a protein that is soluble in orunstable in an aqueous environment, it may be highly desirable toinclude a solubility modulator, that may, for example, be a stabilizingagent, in the composition. Various modulating agents are described inU.S. Pat. Nos. 5,654,010 and 5,656,297 which are incorporated herein byreference. In the case of hGH, for example, it is preferable to includean amount of a salt of a divalent metal, preferably zinc. Examples ofsuch modulators and stabilizing agents, which may form complexes withthe beneficial agent or associate to provide the stabilizing ormodulated release effect, include metal cations, preferably divalent,present in the composition as magnesium carbonate, zinc carbonate,calcium carbonate, magnesium acetate, magnesium sulfate, zinc acetate,zinc sulfate, zinc chloride, magnesium chloride, magnesium oxide,magnesium hydroxide, other antacids, and the like. The amounts of suchagents used will depend on the nature of the complex formed, if any, orthe nature of the association between the beneficial agent and theagent. Molar ratios of solubility modulator or stabilizing agent tobeneficial agent of about 100:1 to 1:1, preferably 10:1 to 1:1,typically can be utilized.

Pore forming agents include, biocompatible materials that when contactedwith body fluids dissolve, disperse or degrade to create pores orchannels in the polymer matrix. Typically, organic and non-organicmaterials that are water soluble such as sugars (e.g., sucrose,dextrose), water soluble salts (e.g., sodium chloride, sodium phosphate,potassium chloride, and sodium carbonate), water soluble solvents suchas N-methyl-2-pyrrolidone and polyethylene glycol and water solublepolymers (e.g., carboxmethylcellulose, hydroxypropylcellulose, and thelike) can conveniently be used as pore formers. Such materials may bepresent in amounts varying from about 0.1% to about 100% of the weightof the polymer, but will typically be less than 50% and more typicallyless than 10-20% of the weight of polymer.

Utility and Administration:

The means of administration of the depot gel compositions is not limitedto injection, although that mode of delivery may often be preferred.Where the depot gel composition will be administered as a leave-behindproduct, it may be formed to fit into a body cavity existing aftercompletion of surgery or it may be applied as a flowable gel by brushingor palleting the gel onto residual tissue or bone. Such applications maypermit loading of beneficial agent in the gel above concentrationstypically present with injectable compositions.

Compositions of this invention without beneficial agent are useful forwound healing, bone repair and other structural support purposes.

To further understand the various aspects of the present invention, theresults set forth in the previously described figures were obtained inaccordance with the following examples.

Example 1 Depot Gel Preparation

A gel vehicle for use in an injectable depot of the composition wasprepared as follows. A glass vessel was tared on a Mettler P13000 toploader balance. Poly (D,L-lactide-co-glycolide) (PLGA), available as50:50 DL-PLG with an inherent viscosity of 0.15 (PLGA-BPI, BirminghamPolymers, Inc., Birmingham, Ala.) and 50:50 Resomer® RG502 (PLGA RG502), was weighed into the glass vessel. The glass vessel containing thepolymer was tared and the corresponding solvent was added. Amountsexpressed as percentages for various polymer/solvent combinations areset forth in Table 1, below. The polymer/solvent mixture was stirred at250±50 rpm (MA electric stirrer, IKH-Werke GmbH and Co., Stanfen,Germany) for about 5-10 minutes, resulting in a sticky paste-likesubstance containing polymer particles. The vessel containing thepolymer/solvent mixture was sealed and placed in a temperaturecontrolled incubator equilibrated to 37° C. for 1 to 4 days, withintermittent stirring, depending on solvent and polymer type and solventand polymer ratios. The polymer/solvent mixture was removed from theincubator when it appeared to be a clear amber homogeneous solution.Thereafter, the mixture was placed in an oven (65 oC) for 30 minutes. Itwas noted that the PLGA was dissolved in the mixture upon removal fromthe oven.

Additional depot gel vehicles are prepared with the following solventsor mixtures of solvents: benzyl benzoate (“BB”), benzyl alcohol (“BA”),ethyl benzoate (“EB”), BB/BA, BB/Ethanol, BB/EB and the followingpolymers: Poly (D,L-lactide-co-glycolide) 50:50 Resomer® RG502, code0000366, Poly (D,L-lactide-co-glycolide) 50:50 Resomer® RG502H,PLGA-502H, code no. 260187, Poly D,L Lactide (Resomer® R 202, Resomer® R203); Poly dioxanone (Resomer® X 210) (Boehringer Ingelheim Chemicals,Inc., Petersburg, Va.); DL-lactide/glycolide 100:0 (MEDISORIB® Polymer100 DL High, MEDISORB® Polymer 100 DL Low); DL-lactide/glycolide 85/15(MEDISORB® Polymer 8515 DL High, MEDISORB® Polymer 8515 DL Low);DL-lactide/glycolide 75/25 (MEDISORB® Polymer 7525 DL High, MEDISORB®Polymer 7525 DL Low); DL-lactide/glycolide 65/35 (MEDISORB® Polymer 6535DL High, MEDISORB® Polymer 6535 DL Low); DL-lactide/glycolide 54/46(MEDISORB® Polymer 5050 DL High, MEDISORB® Polymer 5050 DL Low); andDL-lactide/glycolide 54/46 (MEDISORB® Polymer 5050 DL 2A(3), MEDISORB®Polymer 5050 DL 3A(3), MEDISORB® Polymer 5050 DL 4A(3)) (MedisorbTechnologies International L.P., Cincinnati, Ohio); and PolyD,L-lactide-co-glycolide 50:50; Poly D,L-lactide-co-glycolide 65:35;Poly D,L-lactide-co-glycolide 75:25; Poly D,L-lactide-co-glycolide85:15; Poly DL-lactide; Poly L-lactide; Poly glycolide; Polyε-caprolactone; Poly DL-lactide-co-caprolactone 25:75; and PolyDL-lactide-co-caprolactone 75:25 (Birmingham Polymers, Inc., Birmingham,Ala.).

Example 2 hGH Particle Preparation

Human growth hormone (hGH) particles (optionally containing zincacetate) were prepared as follows: hGH solution (5 mg/ml) solution inwater (BresaGen Corporation, Adelaide, Australia) was concentrated to 10mg/mL using a Concentration/Dialysis Selector diafiltering apparatus.The diafiltered hGH solution was washed with 5 times volume of tris orphosphate buffer solution (pH 7.6). Particles of hGH were then formed byspray drying or lyophilization using conventional techniques. Phosphatebuffer solutions (5 or 50 mM) containing hGH (5 mg/mL) (and optionallyvarious levels of zinc acetate (0 to 30 mM) when Zn complexed particleswere prepared) were spray-dried using a Yamato Mini Spray dryer set atthe following parameters:

Spray Dryer Parameter Setting Atomizing Air    2 psi Inlet Temperature 120° C. Aspirator Dial 7.5 Solution Pump 2-4 Main Air Valve 40-45 psihGH particles having a size range between 2-100 microns were obtained.Lyophilized particles were prepared from tris buffer solutions (5 or 50mM: pH 7.6) containing hGH (5 mg/mL) using a Durastop μP Lyophilizer inaccordance with the following freezing and drying cycles;

Freezing Ramp down at 2.5 C./min to −30° C. and hold for 30 min cycleRamp down at 2.5 C./min to −30° C. and hold for 30 min Drying Ramp up at0.5 C./min to 10° C. and hold for 960 min cycle Ramp up at 0.5 C./min to20° C. and hold for 480 min Ramp up at 0.5 C./min to 25° C. and hold for300 min Ramp up at 0.5 C./min to 30° C. and hold for 300 min Ramp up at0.5 C./min to 5° C. and hold for 5000 minhGH particles having a size range between 2-100 microns were obtained.

Example 3 hGH-Stearic Acid Particle Preparation

Human growth hormone (hGH) particles were prepared as follows:Lyophilized hGH (3.22 grams, Pharmacia-Upjohn, Stockholm, Sweden) andstearic acid (3.22 grams, 95% pure, Sigma-Aldrich Corporation, St.Louis, Mo.) were blended and ground. The ground material was compressedin a 13 mm round die, with a force of 10,000 pounds for 5 minutes.Compressed tablets were ground and sieved through a 70 mesh screenfollowed by a 400 mesh screen to obtain particles having a size rangebetween 38-212 microns.

Example 4 Bupivacaine Base Preparation

Bupivacaine hydrochloride (Sigma-Aldrich Corporation, St. Louis, Mo.)was dissolved in de-ionized (DI) water at a concentration of 40 mg/ml(saturation). A calculated amount of sodium hydroxide (1 N solution) wasadded to the solution and the pH of the final mixtures was adjusted to10 to precipitate the BP bate. The precipitated product was filtered,and further washed with DI water for at least three times. Theprecipitated product was dried at approximately 40° C. in vacuum for 24h.

Example 5 Bupivacaine Particle Preparation

Bupivacaine drug particles using bupivacaine hydrochloride(Sigma-Aldrich Corporation, St. Louis, Mo.) or bupivacaine base preparedaccording example 4 and hydrochloride salt, were prepared as follows.Bupivicaine was grounded and then sieved to a fixed range using 3″stainless steel sieves. Typical ranges include 25 μm to 38 μm, 38 μm to63 μm, and 63 μm to 125 μm.

Example 6 Bupivacaine-Stearic Acid Particle Preparation

Bupivacaine particles were prepared as follows: Bupivacainehydrochloride (100 g, Sigma-Aldrich Corporation, St. Louis, Mo.) wasgrounded and sieved through 63-125 micron sieves. The bupivacaineparticles and stearic acid (100 g, 95% pure, Sigma-Aldrich Corporation,St. Louis, Mo.) were blended and ground. The ground material wascompressed in a 13 mm round die, with a force of 5,000 pounds for 5minutes. Compressed tablets were ground and sieved through a 120 meshscreen followed by a 230 mesh screen to obtain particles having a sizerange between 63-125 microns.

Example 7 Drug Loading

Particles comprising beneficial agent with or without stearic acidprepared as above were added to a gel vehicle in an amount of 10-30% byweight and blended manually until the dry powder was wetted completely.Then, the milky light yellow particle/gel mixture was thoroughly blendedby conventional mixing using a Caframo mechanical stirrer with anattached square-tip metal spatula. Resulting formulations areillustrated in Tables 1, 2 and 3 below.

TABLE 1 PLGA RG502^(a) LMW PLGA^(b) Benzyl Benzoate Formulation (wt %)(wt %) (wt %) 1^(c) 45 0 45 2^(c) 0 45 45 3^(d) 45 0 45 4^(d) 0 45 45^(a)= PLGA RG 502, MW = 16,000. ^(b)= Low Molecular Weight (LMW, MW =8000) PLGA with an ester end group. ^(c)= 10% bupivacaine hydrochlorideloading. ^(d)= 10% bupivacaine base loading.

TABLE 2 PLGA RG502^(a) LMW PLGA^(e) Benzyl Benzoate Formulation (wt %)(wt %) (wt %) 5^(f) 45 0 45 6^(f) 0 45 45 7^(f) 0 63 27 ^(a)= PLGA RG502, MW = 16,000. ^(e)= Low Molecular Weight (LMW, MW - 7,000) PLGA withan ester end group. ^(f)= 5% hGH loading.

TABLE 3 LMW LMW Benzyl Benzyl PLGA^(g) PLGAc^(h) Benzoate AlcoholFormulation (wt %) (wt %) (wt %) (wt %)  8^(i) 58.5 0 31.5 0  9^(i) 58.50 0 31.5 10^(i) 67.5 0 0 22.5 11^(i) 0 67.5 22.5 12^(j) 0 60 20 ^(g)=Low Molecular Weight (LMW, MW = 8,000) PLGA with an ester end group.^(h)= Low Molecular Weight (LMW, MW = 10,000) PLGA with a carboxyl endgroup. ^(i)= 10% bupivacaine hydrochloride loading. ^(j)= 10%bupivacaine hydrochloride and 10% SA loading.

A representative number of implantable depots gel compositions wereprepared in accordance with the foregoing procedures and tested for invitro release of beneficial agent as a function of time and also in invivo studies in rats to determine release of the beneficial agent asdetermined by blood plasma concentrations of beneficial agent as afunction of time.

Example 8 Bupivacaine In Vivo Studies

In vivo studies in rats (4 or 5 per group) were performed following anopen protocol to determine plasma levels of bupivacaine upon systemicadministration of bupivicaine via the implant systems of this invention.Depot gel bupivacaine formulations were loaded into customized 0.5 ccdisposable syringes, Disposable 18 gauge needles were attached to thesyringes and were heated to 37° C. using a circulator bath. Depot gelbupivacaine formulations were injected into rats and blood was drawn atspecified time intervals (1 hour, 4 hours and on days 1, 2, 5, 7, 9, 14,21 and 28) and analyzed for bupivacaine using LC/MS.

FIGS. 1, 2 and 3 illustrate representative in vivo release profiles ofbupivacaine hydrochloride and bupivacaine base obtained in rats fromvarious depot formulation, including those of the present invention. Thein vivo release profile of the depot formulations with low molecularweight PLGA (formulations 2 and 4 in FIGS. 1, 2 and 3) exhibited shortrelease duration for approximately 7 days, comparable to the controlformulations (with higher molecular weight PLGA). Thus, the injectabledepot gel formulations of the invention comprising low molecular weightpolymers provide a controlled, sustained release of a beneficial agentover a short duration of time equal to or less than two weeks.

Example 9 hGH In Vivo Studies

In vivo hGH studies in rats were performed following an open protocol todetermine serum levels of hGH upon systemic administration of hGH viathe injectable depot gel compositions of this invention. Depot gel hGHformulations were loaded into customized 0.5 cc disposable syringes.Disposable 16 gauge needles were attached to the syringes and wereheated to 37° C. using a circulator bath. Depot gel hGH formulationswere injected into immunosuppressed rats and blood was drawn atspecified time intervals. All serum samples were stored at 4° C. priorto analysis. Samples were analyzed for intact hGH content using a radioimmuno assay (RIA).

FIGS. 4, 5 and 6 illustrate representative in vivo release profiles ofhuman growth hormone (“hGH”) obtained in rats from various depotformulation, including those of the present invention. The in vivorelease profile of the depot formulations with low molecular weight PLGA(formulations 6 and 7 in FIGS. 4, 5 and 6) exhibited short releaseduration for approximately 7-14 days, comparable to the controlformulations (with higher molecular weight PLGA). Thus, the injectabledepot gel formulations of the invention comprising low molecular weightpolymers provide a controlled, sustained release of a beneficial agentover a short duration of time equal to or less than two weeks.

Example 10 In Vivo Studies on Bupivacaine Depot Formulation

As illustrated in Table 3, various depot formulations can be made fromthe low molecular weight PLGA with either an ester end group or acarboxyl end group using different solvents such as benzyl benzoate(BB), benzyl alcohol (BA), ethyl benzoate (EB), mixtures of BB/Ethanol,BB/BA, BB/EB etc., with varying polymer/solvent ratios. The drugparticles can be made either with or without hydrophobic excipients suchas stearic acid (SA).

FIG. 7 illustrates representative in vivo release profiles ofbupivacaine obtained in rats from depot formulations made of lowmolecular weight PLGA in either BB or BA. FIG. 8 illustratesrepresentative in vivo release profiles of bupivacaine obtained in ratsfrom depot formulations made of low molecular weight PLGA in BA withvarious polymer/solvent ratios. FIG. 9 illustrates representative invivo release profiles of bupivacaine obtained in rats from depotformulations made of low molecular weight PLGA in BA with different endgroups. FIG. 10 illustrates representative in vivo release profiles ofbupivacaine obtained in rats from depot formulations made of lowmolecular weight PLGA in BA with the drug particles formulated eitherwith or without SA.

As illustrated in this example, by using low molecular weight PLGAeither end-capped with an ester or carboxyl group, the short durationrelease of active agent from depot can be achieved. The formulations canbe made in various solvents or solvent mixtures with variouspolymer/solvent ratios. The release profiles of the active agent fromthe depots can be varied accordingly.

Example 11 Differential Scanning Calorimeter (DSC) Measurements on PLGAPolymers

The glass transition temperature of various low molecular PLGA polymersused in the present invention was determined using a differentialscanning calorimeter (DSC) (Perkin Elmer Pyris 1, Shelton, Conn.). TheDSC sample pan was tarred on a Mettler P13000 top loader balance. Atleast 20 mg of polymer sample was placed in the pan. The weight of thesample was recorded. The DSC pan cover was positioned on to the pan anda presser was used to seal the pan. The temperature was scanned in 10°C. increments from −50° C. to 90° C.

FIGS. 11 and 12 illustrate the differences in the DSC diagrams of lowmolecular weight PLGA used in the formulations presented in thisinvention end-capped with either an ester group or the carboxylterminated. These data demonstrate that the low molecular weight PLGApolymers used in this invention have a glass transition temperatures(“Tg”) above 30° C.

Example 12 In Vitro Degradation of PLGA Polymers

The degradation profiles of low molecular weight PLGA polymers used inthe present invention were performed in vitro at 37° C. in PBS buffer todetermine the mass loss rate of the PLGA polymer as a function of time.Each of the copolymers comprised one sample set. Approximately 25 discs(100±5 mg each) were pressed using a 13 mm stainless steel die. Thesample was pressed with 10 tons of force for approximately 10 minutesusing the Carver Press. The discs were kept in a glass vial in a vacuumoven at ambient temperature and 25 mm Hg until ready for use in thedegradation bath. This procedure was repeated for each polymer tested.Phosphate buffered saline (PBS) solution (50 mM, pH 7.4) with sodiumazide (0.1N) was prepared. One sample disc was weighed into the tarredvial and recorded as initial weight (M_(initial)). PBS (10 mL) waspipetted into each vial. The vial was capped securely and placed in a37° C. shaking water bath. The buffer was changed twice a week, prior towhich the pH of the solution was recorded. At pre-designated timepoints, the samples were removed from the buffer bath, rinsed withde-ionized Milli-Q water, dried superficially, and weighed. The sampleweight was recorded as wet weight (M_(wet)). The sample was placed in a10 mL lyophilization vial and placed in a freezer (−20° C.) prior tolyophilization. After lyophilization, the samples were weighed again andrecorded as dry weight (M_(lyophilized)). The percent mass loss wasdefined as {(M_(lyophilized)−M_(initial))/M_(initial)}×100%.

FIG. 13 illustrates the mass loss profiles of the three PLGAs used inthe formulations described above. From this it can be seen that each ofthe three polymers used has significantly different degradation rates.The low molecular weight PLGA with either an ester end group or carboxylend group have a significantly faster degradation rate than the one withhigher molecular weight. This represents more favorable towards shortduration depots which prefers the polymer degrades as soon as the activeagents are released from the depot. In accordance with various aspectsof the present invention, one or more significant advantages can beobtained. More specifically, using simple processing steps, one canobtain a depot gel composition that can be injected into place in ananimal without surgery using a low dispensing force through standardneedles. Once in place, the composition will quickly return to itsoriginal viscosity and may exhibit rapid hardening so as tosubstantially avoid a burst effect and provide the desired beneficialagent release profile. Furthermore, once the beneficial agent has beenfully administered, there is no need to remove the composition since itis fully biodegradable. As a still further advantage, the presentinvention avoids the use of microparticle or microcapsulation techniqueswhich can degrade certain beneficial agents, like peptide and nucleicacid-based drugs and which microparticles and microcapsules may bedifficult to remove from the environment of use. Since the viscous gelis formed without the need for water, temperature extremes, or othersolvents, suspended particles of beneficial agent remain dry and intheir original configuration, which contributes to the stability ofthereof. Further, since a mass is formed, the injectable depot gelcomposition may be retrieved from the environment of use if desired.

The above-described exemplary embodiments are intended to beillustrative in all respects, rather than restrictive, of the presentinvention. Thus the present invention is capable of many variations indetailed implementation that can be derived from the descriptioncontained herein by a person skilled in the art. All such variations andmodifications are considered to be within the scope and spirit of thepresent invention.

We claim:
 1. A method of administering bupivacaine base orpharmaceutically acceptable salt thereof, comprising administering to asubject a composition comprising: a polyorthoester having a weightaverage molecular weight ranging from 3000 to 10,000; triacetin; andbupivacaine base or pharmaceutically acceptable salt thereof in anamount ranging from 1 wt % to 20 wt % of the composition, wherein theweight ratio of polyorthoester to triacetin ranges from 40:60 to 75:25.2. The method of claim 1, wherein the bupivacaine base orpharmaceutically acceptable salt thereof consists of bupivacaine base.3. The method of claim 1, wherein the polyorthoester has a weightaverage molecular weight ranging from 4000 to
 8000. 4. The method ofclaim 2, wherein the polyorthoester has a weight average molecularweight ranging from 4000 to
 8000. 5. The method of claim 1, wherein thebupivacaine base or pharmaceutically acceptable salt thereof is presentin an amount ranging from 2 wt % to 20 wt % of the composition.
 6. Themethod of claim 2, wherein the bupivacaine base is present in an amountranging from 2 wt % to 20 wt % of the composition.
 7. The method ofclaim 3, wherein the bupivacaine base or pharmaceutically acceptablesalt thereof is present in an amount ranging from 2 wt % to 20 wt % ofthe composition.
 8. The method of claim 4, wherein the bupivacaine baseis present in an amount ranging from 2 wt % to 20 wt % of thecomposition.
 9. The method of claim 1, wherein the weight ratio ofpolyorthoester to triacetin ranges from 50:50 to 75:25.
 10. The methodof claim 2, wherein the weight ratio of polyorthoester to triacetinranges from 50:50 to 75:25.
 11. The method of claim 3, wherein theweight ratio of polyorthoester to triacetin ranges from 50:50 to 75:25.12. The method of claim 4, wherein the weight ratio of polyorthoester totriacetin ranges from 50:50 to 75:25.
 13. The method of claim 5, whereinthe weight ratio of polyorthoester to triacetin ranges from 50:50 to75:25.
 14. The method of claim 6, wherein the weight ratio ofpolyorthoester to triacetin ranges from 50:50 to 75:25.
 15. The methodof claim 7, wherein the weight ratio of polyorthoester to triacetinranges from 50:50 to 75:25.
 16. The method of claim 8, wherein theweight ratio of polyorthoester to triacetin ranges from 50:50 to 75:25.17. The method of claim 1, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration equal to or less thantwo weeks.
 18. The method of claim 1, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration ranging from 24 hoursto 2 weeks.
 19. The method of claim 1, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration ranging from 24 hoursto 10 days.
 20. The method of claim 1, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration ranging from 24 hoursto 7 days.
 21. The method of claim 1, wherein the administeringcomprises locally administering.
 22. A method of administeringbupivacaine base or pharmaceutically acceptable salt thereof, comprisingadministering to a subject a composition comprising: a polyorthoesterhaving a weight average molecular weight ranging from 3000 to 10,000; asolvent comprising triacetin and at least one of dimethyl sulfoxide andN-methyl-2-pyrrolidone; and bupivacaine base or pharmaceuticallyacceptable salt thereof in an amount ranging from 1 wt % to 20 wt % ofthe composition, wherein the weight ratio of polyorthoester to solventranges from 40:60 to 75:25.
 23. The method of claim 22, wherein thebupivacaine base or pharmaceutically acceptable salt thereof comprisesbupivacaine base.
 24. The method of claim 22, wherein the polyorthoesterhas a weight average molecular weight ranging from 4000 to
 8000. 25. Themethod of claim 23, wherein the polyorthoester has a weight averagemolecular weight ranging from 4000 to
 8000. 26. The method of claim 22,wherein the bupivacaine base or pharmaceutically acceptable salt thereofis present in an amount ranging from 2 wt % to 20 wt % of thecomposition.
 27. The method of claim 23, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is present in an amount rangingfrom 2 wt % to 20 wt % of the composition.
 28. The method of claim 24,wherein the bupivacaine base or pharmaceutically acceptable salt thereofis present in an amount ranging from 2 wt % to 20 wt % of thecomposition.
 29. The method of claim 25, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is present in an amount rangingfrom 2 wt % to 20 wt % of the composition.
 30. The method of claim 22,wherein the weight ratio of polyorthoester to solvent ranges from 50:50to 75:25.
 31. The method of claim 23, wherein the weight ratio ofpolyorthoester to solvent ranges from 50:50 to 75:25.
 32. The method ofclaim 24, wherein the weight ratio of polyorthoester to solvent rangesfrom 50:50 to 75:25.
 33. The method of claim 25, wherein the weightratio of polyorthoester to solvent ranges from 50:50 to 75:25.
 34. Themethod of claim 26, wherein the weight ratio of polyorthoester tosolvent ranges from 50:50 to 75:25.
 35. The method of claim 27, whereinthe weight ratio of polyorthoester to solvent ranges from 50:50 to75:25.
 36. The method of claim 28, wherein the weight ratio ofpolyorthoester to solvent ranges from 50:50 to 75:25.
 37. The method ofclaim 29, wherein the weight ratio of polyorthoester to solvent rangesfrom 50:50 to 75:25.
 38. The method of claim 22, wherein the bupivacainebase or pharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration equal to or less thantwo weeks.
 39. The method of claim 22, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration ranging from 24 hoursto 2 weeks.
 40. The method of claim 22, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration ranging from 24 hoursto 10 days.
 41. The method of claim 22, wherein the bupivacaine base orpharmaceutically acceptable salt thereof is released from thecomposition in a controlled manner over a duration ranging from 24 hoursto 7 days.
 42. The method of claim 22, wherein the administeringcomprises locally administering.